CA2504350A1 - Apkc isoforms in nervous system disorders and cancer - Google Patents

Abstract

The present invention establishes a link between altered aPKC function and nervous system disorders and cancers, such as Alzheimer's disease (AD) and neuroblastoma. Methods of using aPKC in diagnosis, drug screening and gene therapy in nervous system disorders and cancers are provided.

Description

ATYPICAL PROTEIN KINASE C ISOFORMS IN DISORDERS OF THE
NERVOUS SYSTEM AND CANCER
FIELD OF INVENTION
The invention described in the present application is supported by Grants from National Institute on Aging (contract number 1020171-1-006672) and National Institute of Health (contract number 1018109-1-21883). The government may have some interests in the present invention.
The present invention relates to atypical isoforms of protein kinase C
(aPKC) and their role in the intracellular mislocalization of gene products in nervous system disorders. In particular, the present invention relates to the discovery that aPKC isofonns arc altered in neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson's disease (PD). The present invention is further directed to the use of aPKC in diagnosis, drug screening and treatments, including gene therapy, for neurological and psychiatric disorders.
The present invention also relates to the atypical isoforms of protein kinase C and their role in cancer. In particular, the present invention relates to the discovery that the atypical PKC~ gene is commonly altered in numerous forms of cancer. The present invention is further directed to the use of aPKC in diagnosis, treatment and development of treatments for cancer.
BACKGROUND OF INVENTION
Protein kinase C (PKC) consists of a heterogeneous family of isozymes derived from nine genes divided into three classes: conventional, novel and atypical. The atypical class of isoforms (aPKC), e.g., PKC~ (PKC~I/II) and PKCv/~,, is distinguished from the conventional and novel classes by their insensitivity to calcium and diacylglycerol (DAG), the classical activators of PKC
(Newton, 2003, Biochem J, 361-71). Together with the proteins encoded by par3 and par6 genes, aPKC has been shown to play a critical role in cell polarity (Ohno, 2001, Curr Opin Cell Biol, 13(S): 641-48). Recently, the par3 and par6 genes were also shown to play a role in the formation of neuronal axons (Shi et al., 2003, Cell, 112(1): 63-75). Loss of function of any of par3, par6 and aPKC proteins can result in disruption of cell polarity.
In addition, a role for aPKC in synaptic plasticity, learning and memory has been established (Sacktor et al., 1993, Proc Natl Acad Sci USA
90:8342-46; Osten et al, 1996, Neurosci Letter 221:37-40; Drier et al, 2002, Nat Neurosci 5:316-24; Ling et al, 2002, Neurosci 5:295-96). In long-term potentiation (LTP), a widely studied model for memory, aPKC plays an important role in the two distinct temporal phases. While full-length aPKC forms are activated during the LTP induction phase, a truncated form of aPKC, termed PKM~ (i.e., PKC~II), is activated during the maintenance phase of LTP. PKM~ is identical to PKC~I, except that it lacks an autoinhibitory regulatory domain (Hernandez, et al., 2003, J
Biol Chem 278, 40305-16 and Hirai et al., 2003, Neurosci Lett 348, 151-54).
Although all of the PKC isoforms can theoretically have PKM forms (i.e., truncated or independent catalytic domains of PKC), the only PKM form that is consistently ' observed in the normal brain is PKM~ (Sacktor et al., 1993). Recent work has shown that PKM~ is both necessary and sufficient for long-term potentiation (LTP) maintenance (Zing et al). Furthermore, expression of PKM~ prolongs memory in an odor avoidance task in Dy~osophila melafzogaster (Drier et al). Thus, the role of PKM~ in memory appears conserved in widely divergent species. Consistent with this notion, the human form of the PKM~ mRNA has been identified (Hernandez, et al).
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive impairment in memory and cognitive functions.
Imbalances in neuronal signal transduction pathways have been implicated in AD's pathogenesis (Shimohama et al., 1990, J Neural Transm Suppl 30:69-78). Several studies have demonstrated abnormalities of protein kinase C (PKC) function in brain tissue of AD patients (Cole et al., 1988, Brain Res 452:165-174; Clark et al., 1991, Lab Invest 64, 35-44; Horsburgh et al., 1991, J Neurochem 56:1121-1129;
Masliah et al., 1990, J Neurosci 10:2113-24; Masliah et al., 1991, J Neurosci 11:2759-2767;
Saitoh et al., 1990, Adv Exp Med Biol 265:301-10; Saitoh et al., 1993, Acad Sci 695:34-41; Shimohama et al., 1993, Neurology 43:1407-1413; Lanius et al., 1997, Brain Res 764:75-80; Wang et al., 1994, Neurobiol Aging 15:293-298).
Microscopically, the two major features of AD are the presence of (3-amyloid (A (3) containing senile plaques (SP) and tau containing neurofibrillary tangles (rdFT). Amyloid angiopathy, defined as amyloid deposition in blood vessels, also occurs to a varying extent. Other changes include granulovacuolar degeneration (GVD) and Hirano body (HB) formation.
The NFT are abnormal structures, composed mainly of paired helical filaments (PHFs) consisting of a hyperphosphorylated form of the microtubule-associated protein tau (Buee et al., 2000, Braiyz Res Braifz Res Rev 33, 95-130). The distribution of tau is largely restricted to axons, where it functions mainly to stabilize microtubules (MT) and promote MT polymerization. In NFT-containing neurons, however, tau-associated PHFs can be found throughout the cytoplasm and dendrites. Other components of the NFT include microtubule-associated protein (MAP2) and ubiquitin. A "ghost tangle" is a type of NFT, where the surrounding neuron has completely degenerated. Ghost tangles can contain deposits of A[3 that accumulate after cell death. PHFs also exist in dystrophic neurites surrounding the senile plaques as well as in other neurites, where they are termed neuropil threads.
In addition to AD, at least 20 different diseases have tau-based neurofibrillary pathology as a feature and are collectively known as tauopathies (Lee et al., 2001, Anrau Rev Neunosci 24, 1121-59). This group includes AD, Pick's disease (PiD), frontotemporal dementia with Parkinsonism linked to chromosome (FTDP-17), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Considerable heterogeneity exists between the tangles found in the various tauopathies. For example, NFT in AD are composed principally of PHFs with a diameter of 8-20 nm; some straight filaments are also seen in AD. In contrast, the tangles of FTDP-17 are twisted and straight, but not paired and helical.
Nevertheless, the tau protein in all these disorders is hyperphosphorylated.
It has been argued that tau-based tangle formation is not the primary pathological event in AD since tangles appear in a number of other disorders.
This apparent lack of specificity suggests that the NFT is a final endpoint of a number of pathophysiologic processes rather than an initiating event. Contrary to this view, it has been discovered that a mutation in the tau gene itself in multiple FTDP-17 family lineages can lead to tau dysfunction and degeneration in the absence of A(3 accumulation (Lee et al., 2001).
NFT develop through stages (Braak et al., 1994, Acta Neuropathol 87, 554-67). The earliest form of NFT is the pre-NFT, where PHFs begin to form, but the full tangle has not yet developed. The next is the intracellular stage, where the cytoplasm becomes filled with hyperphosphorylated tau. The final stage is the "extracellular" NFT, where cell death has occurred, the membrane and organelles cleared away, but the cytoskeletal remnants remain. The final stage is also referred to as "ghost" tangles. Using phosphospecific tau antibodies, it was discovered that the pattern of tau phosphorylation varies between these three different stages (Augustinack et al., 2002, Acta Neuf°opathol (Berl) 103, 26-35).
Theoretically, if one knows which residues on tau are phosphorylated first, then one can have a better chance at identifying the kinase responsible for the tau phosphorylation. It was demonstrated that T153, 5262 and T231 were among the first residues in tau to become phosphorylated stages (Augustinack et al., 2002).
Despite extensive research, the particular kinase that phosphorylates tau in AD has not been clearly identified (Buee et al., 2000). The longest tau protein isoform contains 79 possible serines and threonines, with phosphoiylation of least 30 of them occurring in AD. Numerous kinases have been shown to phosphorylate tau in vitro, but leading candidate kinases have been shown to phosphorylate tau ih vivo. These are glycogen synthase kinase 3(3 (GSK3(3) and cyclin-dependent kinase (cdk5). Both are members of a group of proline-directed kinases that prefer serine/threonine residues directly followed by a proline. Abnormal tau from an AD
brain contains a mixture of hyperphosphorylated serine and threonine residues with and without a trailing proline: Indeed, researchers have postulated multiple kinases phophorylating tau at different sites, which can be proline directed and non-proline directed protein kinases.
The conventional PKCoc isoform can phosphorylate the cytoskeletal protein tau. It is not the full-length form of PKCa,, but the truncated PKMa form of the enzyme which is selectively capable of phosphorylating tau (Cressman et al., 1995, M. FEBS Letter 367, 223-27). The only PKM isoform that is consistently overserved in the brain is PKM~ (Naik et al., 2000, J Comp Neurol., 426(2):243-58).
The present invention, for the first time, shows that PKM~ directly phosphorylates tau. For this reason, increases in aPKC will cause NFT
formation.
Furthermore, aPKC phosphorylates GSK3[3, a kinase well known to phosphorylate tau, leading to inactivation of GSK3(3 (Lavoie et al., 1999, JBiol Chem 274, 85). For this reason, decreases in aPKC activity constitute a removal of the negative regulation of GSK3(3 activity and indirectly causes NFT formation. The present invention provides that apkc and gsk3b, both known regulators of cell polarity, are present in a complex. Alterations in the signaling or activity of these two kinases leads to mislocalization of gene products within the intracellular and extracellular compartments as well as abnormal posttranslational modifications of gene products and subsequent pathology including neurological dysfunction and cancer.
While the etiology of cancer is heterogenous, and largely depends on the tissue type, there is a consensus among those skilled in the art that human cancer cells show a markedly increased genetic mutation rate (genetic instability).
The mutations can manifest themselves as chromosomal abnormalities (e.g.
deletions, insertions, amplifications, mutations and rearrangements) and point mutations.
The effects of such genomic alterations are varied; but some of these alterations are direct contributors to cancer development. Cancer develops through stages. The early stages tend to be more benign, with a better prognosis. In contrast; the later stages are more malignant, and tend to metastasize to a larger extent. Late stage cancers tend to have accumulated more chromosomal alterations. The present .
invention utilizes alterations in the aPKC genes and their RNA or protein products to diagnose, stage, treat, and develop treatments for cancer.
One example of a chromosomal alteration associated with cancer development is deletion of the short arm of chromosome 1 (lp). Chromosome lp deletions have been observed in a wide variety of cancers. It has been estimated that over one half of solid tumors are associated with chromosome lp deletions. The current method for determining the status of chromosome lp in tumors involves fluorescence in situ hybribization (FISH). While highly sensitive, FISH has numerous drawbacks including the fact that it is not routinely used in pathology laboratories, is costly and time consuming. The present invention provides a new way to determine the status of chromosome lp in tumors using probes to the PKC~
gene, such as antisera. Antisera based methods are routinely used in pathology laboratories, are robust and inexpensive. For this reason, PKC~ gene status is by far superior to FISH in determining cancer status.
The PKC~ gene lies on the short arm of the first chromosome (1p36.33). 'The gene lies a relatively short distance, about 2 million base pairs, away from the telomere. The proximity of the PKC~ gene to the telomere should theoretically make it susceptible to chromosomal deletion and rearrangement.
It is demonstrated by the present invention that the presence or absence of aPKC in cancers is useful for their diagnosis and staging.
The effect of deletion of chromosome lp varies depending on the tumor type. For example, deletion of lp in oligodendroglioma is a favorable prognostic indicator. In contrast, chromosome lp deletion in neuroblastoma is considered unfavorable. As demonstrated by the present invention, one skilled in the art can now determine the status of chromosome lp using specific probes to PKC~. Examples of such probes include antisera, complimentary DNA or RNA
sequences to aPKC, or PCR primers. The presence or absence of PKC~ is effective in determining the variety, stage or grade of the tumor.
SUMMARY OF THE INVENTION
The present invention demonstrates that an increase or a decrease in V~ ' aPKC activity can lead to the development of pathological changes in cells, leading --to nervous system dysfunction and cancer. It is contemplated by the presented invention that alteration in aPKC signaling contributes to the pathogenesis of nervous system disorders, such as Alzheimer Disease (AD). Accordingly, the localization of aPKC in NFT and the fact that disruption in aPKC signaling causes tau phosphorylation establish that aPKC alterations participate in pathogenesis of nervous system disorders. The present invention thus provides aPKC as a novel target for rational drug design useful for modulating aPKC activity for the purpose of treating nervous system disorders. The present invention further provides methods for diagnosis of nervous system disorders.
Specifically, it has been discovered by the present invention that PKM~, a key molecule in the maintenance of long-term potentiation (LTP) and memory formation, e.g., in Drosophila, colocalizes with the NFT. Accordingly, disruption in PKM~ signaling contributes to the pathogenesis of nervous system disorders, such as AD. The presence of PKM~ protein in the human brain is also demonstrated by the present invention.
In accordance with the present invention, one aspect of the present invention is the identification of atypical isoforms of protein kinase C
(aPKC), e.g.
PKM~, and their role in nervous system disorders, such as AD.
Another aspect of the present invention provides a method for diagnosing nervous system disorders, such as AD. According to the present invention, a method for diagnosing neurological dysfunctions or nervous system disorders in a subject, using an aPKC specific probe, is provided. The diagnostic method of the present invention includes the steps of a. contacting a sample from the subject, e.g. a tissue biopsy, cerebrospinal fluid (CSF), or a blood sample, with an aPKC specific probe, b. detecting the binding of the probe to the sample to determine the amount, localization or activity of the aPKC in the sample, c. contacting a control sample with the aPKC specific probe, d. detecting the binding of the probe to the control sample, e.g. a tissue biopsy, CSF, or a blood sample, to determine the amount, localization or activity of the aPKC in the control sample, and e. comparing the amount, localization or activity of the saPKC in Step b with the amount, localization or activity of the aPKC in Step d, whereby if the amount, localization or activity of the aPKC in Step b is different from the amount, localization or activity of the aPKC in Step d, a nervous system disorder in the subject is present.
Still another aspect of the present invention provides methods for screening drugs or molecular compounds useful for modulating the amount or activity of the aPKC. According to the present invention, a method for screening molecular compounds, e.g. peptides and small molecules, using cells and aPKC
specific probes is provided. Such method includes:
a. providing cells wherein aPKC gene is expressed, b. incubating the cells with a candidate compound for a sufficient time to induce a change in the amount, localization or activity of aPKC in the cells, c. incubating the cells as in Step b, in the absence of the candidate compound, d. contacting the cells from Step b and Step c with an equal amount of an aPKC-specific probe, e. detecting the binding of the probe to the cells to determine the amount, localization or activity of the aPKC in the cell from Step b and Step c, and f. comparing the amount, localization or activity of the aPKC in the cells, wherein if the amount, localization or activity of the aPKC in the cells from Step b is different from the amount, localization or activity of the aPKC in the cells from Step c, the candidate compound is identified as a compound that modulates aPKC.
An alternate method for screening molecular compounds for use in treatment of brain disorders involves the over-expression or deletion of genetic elements containing atypical PKC sequences in cells or animals, e.g. mice, and assaying said cells or animals for atypical PKC activity or levels.
In a further aspect of the present invention, an irZ vitro cell-free method for screening drugs or molecular compounds useful for modulating the amount, localization or activity of the aPKC, using aPKC and a substrate, is provided. Such method includes:
a. incubating an aPKC in a first container with adenosine triphosphate (ATP), preferably radioactively labeled ATP, a substrate of the aPKC, e.g. protein tau, with a candidate compound, for a sufficient time to induce a change in the amount or activity of the aPKC in the first container, b. incubating the aPKC in a second container with ATP, preferably radioactively labeled ATP, and the substrate of said aPKC, e.g. protein tau, for a sufficient time to induce a change in the amount or activity of aPKC in the second container, c. quantifying the amount of incorporation of the phosphate into the substrate in the first container and the second container, and d. comparing the amount of incorporation in the first container and the second container, whereby a difference in the amount of incorporation in the first container and the second container inindicates that the candidate compound is identified as a compound modulating aPKC amount, localization or activity.
A variation of this method involves using a phospho-specific antisera to quantify phosphate incorporation into the substrate.
In still a further aspect of the present invention, methods, including gene therapy, for treating and/or preventing neurological disorders are provided.
According to the present invention, a method for treating and/or preventing neurological dysfunction is provided which employs a sequence corresponding to an aPKC, e.g. PKM~ (or an antisense sequence of aPKC) and an expression vector.
This method includes the steps of a. inserting the aPKC sequence, e.g. PKM~, into the expression vector, and b. administering the vector to a subject, e.g. a patient, whereby the vector treats and/or prevents a neurological dysfunction.
The methods of the present invention can be employed in the treatment and/or prevention of a variety of neurological disorders characterized by abnormal aPKC activity, such as phosphorylation of protein tau and co-localization with NFT. Such tau-associated filamentous aggregates are neuropathological hallmarks of Alzheimer's disease (AD), Pick's disease (PiD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD), Parkinson's Disease (PD), for example.
In yet a further aspect of the present invention provides antibodies against PKM~ for detection, treatment and/or prevention of neurological disorders, e.g. AD.
Thus, an object of the present invention is to detect, treat and/or prevent neurological disorders, such as Alzheimer's disease.
A further aspect of the present invention provides a method for constructing transgenic animals, such as a knock-out mouse lacking aPKC or a mouse that overexpresses the wild type or a mutant aPKC, that are useful as animal models of neurological dysfunction. The method includes:
a. constructing a transgenic animal having an altered aPKC amount, localization or activity, e.g., by deleting an aPKC gene in the animal using knock-out techniques known to one skilled in the art, b. treating the transgenic animal from Step a with a candidate treatment process, c. treating the transgenic animal from Step a with a control treatment process, d. assaying the transgenic animals from Steps b and c for a biochemical or behavioral change, and e. comparing the results of the assay of the transgenic animals from Steps b and Step c, wherein a difference is indicative the efficacy of the candidate treatment process in alleviating the neurological dysfunction.
A variation of the method involves over-expression of either wild-type or mutated aPKC in a transgenic animal, alone or in combination with one or more other transgenes expressing mutations or polymorphisms in genes associated with neurodegeneration, e.g. superoxide dismutase, tau, (3-amyloid, a-synuclein, and apolipoprotein E.
Still a further aspect of the present invention involves the genetic screening of DNA for mutations or polylnorphisms in the DNA sequence of the aPKC genes, e.g. PKC~I/II and PKCL/~,, and regions regulating the expression of these genes including promoter regions, enhancer regions and negative regulatory regions. A method for such screening includes:
a. isolating DNA from a sample of a subject, b. sequencing an aPKC gene or its regulating region of the DNA from Step a and, c. comparing the DNA sequence from Step b to a reference DNA sequence, wherein the reference DNA is a known normal DNA sequence of the same region as sequenced DNA in Step b but without any mutation, whereby a difference between the DNA sequence from Step b and the reference sequence is indicative of genetic susceptibility to a neurological or psychiatric disorder.
A particular aspect of the present invention is directed to the use of a known aPKC interacting protein for all of the above methods.
In a further aspect, the present invention is directed toward the treatment of other abnormal protein aggregates including a-synuclein seen in PD, multisystem atrophy (MSA) and dementia with Lewy bodies (DLB) and (3-amyloid in AD and normal aging.
In another aspect, the present invention provides methods for diagnosing various forms of cancer, such as neuroblastoma. According to the present invention, a method for diagnosing and/or staging a tumor is provided. The diagnostic method of the invention includes the steps of:

a. contacting an aPKC specific probe, preferably a PKC~ specific probe, with a tumor sample, e. g. a human biopsy sample, from a subject, b. detecting the binding of the probe to the tumor sample to quantify the level, amount or activity of said aPKC in said tumor sample, c. contacting the aPKC specific probe with a control sample, d. detecting the binding of the probe to the control sample to quantify the level, amount or activity of the aPKC in the control sample, and e. comparing the level, amount or activity of the aPKC in Step b with the level, amount or activity of the aPKC in Step d, wherein the difference of the level, amount or activity of the aPKC is indicative of the type and the staging of the tumor.
Still another aspect of the invention provides methods for drug screening for the purpose of treating and/or preventing cancer, e. g.
neuroblastoma.
According to the present invention, a method for screening molecular compounds, e.
g. peptides and small molecules, is provided.
Yet another aspect of the present invention provides methods for treating cancer with gene therapy.
BRIEF DESCRIPTION OF THE FIGURES
Figure lA illustrates that PKC~ phosphorylates the cytoskeletal protein tau. Autoradiogram showing incorporation of radioactive phosphate into tau Lane 1 shows that tau, in the absence of kinase, shows little incorporation of phosphate. Lane 2 and 4 show that in the absence of tau, there is no phosphorylarion. Lane 3 demonstrates that when tau is incubated with PKC~
phosphate is incorporated into tau. Lane 5 was included as a control, since GSK3(3 is well known to be able to phosphorylate tau. Figure 1B illustrates that cotransfection of PKM~ with GSK3(3 into neuroblastoma cells decreases tau phosphorylation. Western blot on protein extracts from neuroblastoma cells (IMR-32) transfected with full-length human tau and the indicated constructs were probed with a phosphospecific anti-tau (p396) antisera. Lane 1 shows that cotransfection of GSK3 ~i results in a prominent degree of phosphorylation of tau on p396. Lane shows that cotransfection with EGFP alone does not result in an increase in phosphorylated tau. Lane 3 shows that transfection with an EGFP-tagged kinase inactive mutant of PKM~ (EGFP-PKM~-KI, K2S 1 W) also fails to result in increased tau phosphorylation. Lane 4 shows that transfection of GSK3(3 and EGFP-tagged PKM~ results in less phosphorylation of tau than GSK3[3 alone (compare with lane 1 ). Lane 5 shows that EGFP-tagged PKM~ is capable of phosphorylating tau (compare with lane 2 and 3) but not to the same degree as GSK3(3 (compare with lane 1). Lane 6 shows that cotransfection of EGFP-PKM~-KI with GSK3(3 also results in decreased tau phosphorylation (compare to lane 1).
Figure 2 illustrates that aPKC co-localizes with NFT. Using specific antisera to all known PKC gene products, immunohistochemistry reveals that only PKC~ and PKCi/~, are present in NFT. Silver stain confirms the presence of NFT
in this tissue, and omitting primary antisera fails to label NFT.
Figure 3A illustrates a Western blot showing reactivity of aPKC
antibodies in hippocampus, caudate nucleus, cerebellum, and superior temporal cortex. PKM~ was seen as a 55 kD band in all regions tested. PKCv/~, was seen as a 72 kD band in all regions tested. Full-length PKC~ was only seen in the cerebellum.
Figure 3B illustrates the stability of aPKC in post-mortem rat brain tissue.
The total level of aPKC was measured using quantitative Western blot with specific antisera to the catalytic domain of PKC~ and PKCi/~,.
Figure 4 illustrates that PKCy and PKCv/~, but not PKM~ decreases in the superior temporal cortex in AD. Figure 4A: Representative Western blots on total protein homogenates from a representative control and AD case. Figure 4B:
Histogram showing mean and standard deviation. * indicates statistical significance.
Figure 5 illustrates that PKCi/~, but not PKM~ or PKCy increase in the caudate nucleus in AD. Figure SA: Representative Western blots on total protein homogenates from a representative control and AD case. Figure SB: Histogram showing mean and standard deviation. * indicates statistical significance.
Figure 6 illustrates localization of aPKC in human cerebral parahippocampal cortex. ~-C1 (Figure 6B). No primary antibody control (Figure 6A). aPKC staining can be seen in perikarya and proximal dendrites. No neuronal nuclear staining was observed. Scale bar = 100 ~,m.
Figure 7 illustrates localization of aPKC in human astrocytes.
Astrocytes stained strongly with antiPKCv/7~ in the cerebral cortex (Figure 7A). ~-C 1 reacted with astrocytes in CA-4 of the hippocampus (Figure 7B). Scale bar =

200~,m. Inset shows high power of an astrocyte. Scale bar = 25 ~.m.
Figure 8 illustrates localization of aPKC in ependymal glia. ~-C 1 reacted with ependyrnal glia (Figure 8B). No primary antibody control (Figure 8A).
bar = 100 Vim.
Figure 9 illustrates that aPKC colocalizes with neuropil threads and dystrophic neurites. Figure 9A: Immunohistochemical stain using z-C2 of paraffin embedded hippocampal cortex from case of AD. Figure 9B: Silver stain from a non-adjacent section. Large arrows indicate SP; small arrows indicate neuropil threads.
bar = 100 Vim.
Figure 10 illustrates that aPKC colocalizes with Hirano bodies (HB) in area CA-1 of the hippocampus. Arrows indicate HB can be seen as a brightly eosinophilic rod-like structure when stained with hematoxylin and eosin (H&E, Figure l0A). HB can be seen with all of the aPKC antibodies, ~-C1 (Figure l OD), y ~-C2 (Figure 1 OB) and v/~, (Figure l OC). bar = 100 ~.m.
Figure 11 illustrates PKM~ distribution correlates with unique brain-specific ~ RNA. Figure 11A: Reverse-transcription polymerise chain reaction (RT-PCR) using specific primers reveal that PKM~ mRNA is abundant only in brain;
PKC~ mRNA is abundant in many other tissues. Figure 11B: RNase protection reveals levels of PKM~ mRNA and PKC~ mRNA in different tissues. Figure 11C:
Northern blot to quantify levels of PKM~ mRNA and PKC~ niRNA in different tissues.
Figure 12 illustrates that treatment of dissociated primary hippocampal neuronal cultures with high potassium results in increased levels of PKM~ (green) reletive to MAP2 (red). Figure 12A: Control culture untreated has low levels of PK1VI~. Figure 12B: Stimulation with high potassium,results in an increase in PKM~.
Figure 13 depicts a Western blot showing the lack of expression of PKC~I/II in neuroblastoma cells (IMR-32 cell line). Lane 1 shows that a rat brain lysate when probed with an anti-PKCi/1 antiserum displays a band at about 72 kD.
Lysates of IMR-32 cells (lane 2) and pheochromocytoma cells (lane 3), when probed with specific anti-PKCv/~, antisera also show PKCi/1. In contrast, when IMR32 and PC12 cells are probed with a specific anti-PKC~I/II antiserum, IMR32 cells have no bands (lane 6), but PC12 cells show multiple bands (lane 7). When IMR-32 cells were transfected with PKC~II a doublet of two bands was detected for PKC~II at around 80 kDa (lane 5). In contrast, lysates of IMR-32 cells transfected with EGFP
alone did not contain a band when probed with anti-PKC~II (lane 4).
Figure 14 depicts association of PKCi/~, with tauopathies and a-synucleinopathies. The PKCt/7~ antibody weakly labeled cytoplasm of unremarkable hippocampal neurons and neuropil in a control case (Fig. 14a), while strongly labeling NFTs (Fig. 14b) and Hirano bodies (Fig. 14c) in an AD case.
The antibody also labeled Pick bodies (Fig. 14d) and Pick cells in PiD; globose tangles (Fig. 14e) and tufted glial cells (Fig. 14f) in PSP; and ballooned neurons (Fig. 14g) and astrocytes (Fig. 14h) in CBD. In a-synucleinopathies, the antibody strongly labeled classic Lewy bodies in pigmented substantia nigra neurons (Fig. 14i) and Lewy bodies in amygdala (Fig. 14j) and cortex in PD and-DLB._ In MSA, glial inclusions were also immunoreactive (Fig. 14k). Omission of the primary antibody yielded no staining of any inclusions such as these nigral Lewy bodies (arrow) (Fig.
141).
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to the atypical isoforms of protein kinase C (aPKC) and their participation in intracellular localization and mislocali~ation of cellular components, particularly in human diseases, e.g.
Alzheimer's disease (AD) and cancer.
By "Activity" is meant the ability of an enzyme to act as a catalyst to induce chemical changes in other substances, including the ability to transfer phosphate to substrate molecules as well as to aggregate molecules. "Activity of aPKC" or "aPKC activity" used herein includes, for example, inhibition of aPKC, co-localization of aPKC with neurofibrillary tangles (NFT) or Hirano body (HB) and phosphorylation of protein tau by aPKC. "Activity" used herein can be also referred to the level, amount or localization of the enzyme.
By "control" is meant a normal subject or unchanged chemical, or a subject or a chemical in its normal state. "Control" can also be refered to as a chemical with known properties, for example, in the case of a "positive control."
Thus, a "control" can be referred to as comparison to a reference range which is the normal value.

The PKC gene family consists of at least 10 distinct isoforms with diverse cellular functions (Newton, 2003). Although all of the PKC isoforms can theoretically have truncated PKM forms, the only PKM form that is consistently observed in the brain is PKM~, an atypical member of the PKC family (aPKC) (Sacktor et al). Specifically, it has been discovered by the inventors that PKM~, a key molecule in the maintenance of long-term potentiation (LTP) and memory formation in Drosopl2ila, colocalizes with the NFT. Accordingly, disruption in PKM~ signaling may contribute to the pathogenesis of neurological disorders, such as AD.
By "disruption in PKM~ signaling" is meant increases or decreases in the level, location or activity of the kinase or its effectors, substrates and associated molecules.
"Modulating" or "modulate" used herein also include inhibiting or inhibit and activating or activate.
According to the present invention, alteration in aPKC function can lead to hyperphosphorylation of the cytoskeletal protein tau, see Figure 1.
Also in accordance with the present invention, aPKC colocalizes with the NFT, see Figure 2.
Phosphorylation of tau at sites clustered around the MT binding regions inhibits tau binding to MT. Indeed, the tau found in AD brain and NFT
is hyperphosphorylated at many sites not normally phosphorylated in adult human brain. The present invention recognizes that phosphorylation of tau causes its dissociation from MTs and buildup in the cytoplasm, which in turn could lead to the formation of tau aggregates and ultimately NFT.
In accordance with the present invention, the localization of aPKC to the NFT and the ability of aPKC to phosphorylate tau confirm that aPKC is altered in nervous system disorders, such as AD. Accordingly, co-localization of aPKC, especially PKM~, with NFT strongly suggests aPKC is involved in tau phosphorylation. Accordingly, the present invention employs the activity of aPKC, especially PKM~, and provides compositions and methods that are useful for diagnosis, drug screening and treatment of neurological disorders, such as AD.
"Psychological disorder" refers to a diseases of the mind in the context of human and animal behavior. "Neurological disorder" refers to diseases of the nervous system. "Neurodegenrative disorder" refers to diseases characterized by progressive degeneration of neurons in the nervous system.
Accordingly, the present invention can be employed in detection, diagnosis, treatment, prevention or prognosis of nervous system disorders that include, but are not limited to, Acquired Epileptiform Aphasia, Acute Disseminated Encephalomyelitis, Adrenoleukodystrophy, Agenesis of the corpus callosum, Agnosia, Aicardi syndrome, Alexander disease, Alpers' disease, Alternating hemiplegia, Alzheimer's disease, Amyotrophic lateral sclerosis,Anencephaly, Angelman syndrome, Angiomatosis, Anoxia, Aphasia, Apraxia, Arachnoid Cysts, Arachnoiditis, Arnold-Chiari malformation, Arteriovenous malformation, Asperger syndrome, Ataxia Telangiectasia, Attention Deficit Hyperactivity Disorder, Autism, Autonomic Dysfunction, Back Pain, Batten disease, Behcet's disease, Bell's palsy, Benign Essential Blepharospasm, Benign Focal Amyotrophy, Benign Intracranial Hypertension, Binswanger's disease, Blepharospasm, Bloch-Sulzberger syndrome, Brachial plexus injury, Brain abscess, Brain injury, Brain tumor, Spinal tumor, Brown-Sequard syndrome, Canavan disease, Carpal tunnel syndrome,Causalgia, Central pain syndrome, Central pontine myelinolysis, Cephalic disorder, Cerebral aneurysm, Cerebral arteriosclerosis, Cerebral atrophy, Cerebral gigantism, Cerebral palsy, Charcot-Marie-Tooth disease, Chiari malformation, Chorea, Chronic inflammatory demyelinating polyneuropathy (CIDP), Chronic pain, Chronic regional pain syndrome, Coffin Lowry syndrome, Coma, including Persistent Vegetative State, Congenital facial diplegia, Corticobasal degeneration, Cranial arteritis, Craniosynostosis, Creutzfeldt-Jakob disease, Cumulative trauma disorders, Cushing's syndrome, Cytomegalic inclusion body disease (CIBD), Cytomegalovirus Infection, Dancing eyes-dancing feet syndrome, Dandy-Walker syndrome, Dawson disease, De Morsier's syndrome, Dejerine-Klumpke palsy, Dementia, Dermatomyositis, Diabetic neuropathy, Diffuse sclerosis, Dysautonomia, Dysgraphia, Dyslexia, Dystonias, Early infantile epileptic encephalopathy, Empty sella syndrome, Encephalitis, Encephaloceles, Encephalotrigeminal angiomatosis, Epilepsy, Erb's palsy, Essential tremor, Fabry's disease, Fahr's syndrome, Fainting, Familial spastic paralysis, Febrile seizures, Fisher syndrome, Friedreich's ataxia, Gaucher's disease, Gerstmann's syndrome, Giant cell arteritis, Giant cell inclusion disease, Globoid cell Leukodystrophy, Guillain-Barre syndrome, HTLV-1 associated myelopathy, Hallervorden-Spatz disease, Head injury, Headache, Hemifacial Spasm, Hereditary Spastic Paraplegia, Heredopathia atactica polyneuritiformis, Herpes zoster oticus, Herpes zoster, Hirayama syndrome, Holoprosencephaly, Huntington's disease, Hydranencephaly, Hydrocephalus, Hypercortisolism, Hypoxia, hnmune-Mediated encephalomyelitis, Inclusion body myositis, Incontinentia pigmenti, Infantile phytanic acid storage disease, Infantile Refsum disease, Infantile spasms, Inflammatory myopathy, Intracranial cyst, Intracranial hypertension, Joubert syndrome, Kearns-Sayre syndrome, Kennedy disease, Kinsbourne syndrome, Klippel Feil syndrome, Krabbe disease, Kugelberg-Welander disease, Kuru, Lafora disease, Lambert-Eaton myasthenic syndrome, Landau-Kleffner syndrome, Lateral medullary (Wallenberg) syndrome, Learning disabilities, Leigh's disease, Lennox-Gastaut syndrome, Lesch-Nyhan syndrome, Leukodystrophy, Lewy body dementia, Lissencephaly, Locked-In syndrome, Lou Gehrig's disease,Lumbar disc disease, Lyme disease - Neurological Sequelae, Machado=Joseph disease, Macrencephaly, Megalencephaly, Melkersson-Rosenthal syndrome, Menieres disease, Meningitis, Menkes disease, Metachromatic leukodystrophy, Microcephaly, Migraine, Miller Fisher syndrome, Mini-Strokes, Mitochondrial Myopathies, Mobius syndrome, Monomelic amyotrophy, Motor Neurone Disease, Moyamoya disease, Mucopolysaccharidoses, Multi-Infarct Dementia, Multifocal motor neuropathy, Multiple sclerosis, Multiple system atrophy with postural hypotension, Muscular dystrophy, Myasthenia gravis, Myelinoclastic diffuse sclerosis, Myoclonic encephalopathy of infants, Myoclonus, Myopathy, Myotonia congenita, Narcolepsy, Neurofibromatosis, Neuroleptic malignant syndrome, Neurological manifestations of AIDS, Neurological sequelae of lupus, Neurological Sequelae of Lyme disease, Neuromyotonia, Neuronal ceroid lipofuscinosis, Neuronal migration disorders, Niemann-Pick disease, O'Sullivan-McLeod syndrome, Occipital Neuralgia, Occult Spinal Dysraphism Sequence, Ohtahara syndrome, Olivopontocerebellar Atrophy, Opsoclonus Myoclonus,/ Optic neuritis, Orthostatic Hypotension, Overuse syndrome, Pain - Chronic, Paresthesia, Parkinson's disease, Paramyotonia Congenita, Paraneoplastic diseases, Paroxysmal attacks, Parry Romberg syndrome, Pelizaeus-Merzbacher disease, Periodic Paralyses, Peripheral Neuropathy, Persistent Vegetative State, Pervasive Developmental Disorders, Photic sneeze reflex, Phytanic Acid Storage disease, Pick's disease, Pinched Nerve, Pituitary Tumors, Polymyositis, Porencephaly, Post-Polio syndrome, Postherpetic Neuralgia, Postinfectious Encephalomyelitis, Postural Hypotension, Prader-Willi syndrome, Primary Lateral Sclerosis, Prion diseases, Progressive Hemifacial Atrophy, Progressive multifocal leukoencephalopathy, Progressive Sclerosing Poliodystrophy, Progressive Supranuclear Palsy, Pseudotumor cerebri, Ramsay-Hunt syndrome, Ramsay Hunt syndrome Type I, Ramsay Hunt syndrome Type II, Rasmussen's Encephalitis, Reflex Sympathetic Dystrophy syndrome, Refsum disease - Infantile, Refsum disease, Repetitive Motion Disorders, Repetitive Stress Injuries, Restless Legs syndrome, Retrovirus-Associated Myelopathy, Rett syndrome, Reye's syndrome, Saint Vitus Dance, Sandhoff disease, Schilder's disease, Schizencephaly, Septo-Optic Dysplasia, Shaken Baby syndrome, Shingles, Shy-Drager syndrome, Sjogren's syndrome, Sleep Apnea, Soto's syndrome, Spasticity, Spina bifida, Spinal Cord injury, Spinal Cord Tumors, Spinal Muscular Atrophy, Stiff Person syndrome, Stroke, Sturge-Weber syndrome, Subacute Sclerosing Panencephalitis, Subcortical Arteriosclerotic Encephalopathy, Sydenham Chorea, Syncope, Syringomyelia, Tardive Dyskinesia, Tay-Sachs disease, Temporal arteritis, Tethered Spinal Cord syndrome, Thomsen disease, Thoracic Outlet syndrome, Tic Douloureux, Todd's Paralysis, Tourette syndrome, Transient ischemic attack, Transmissible Spongiform Encephalopathies, Transverse myelitis, Traumatic Brain injury, Tremor, Trigeminal Neuralgia, Tropical Spastic Paraparesis, Tuberous Sclerosis, Vasculitis including Temporal Arteritis, Von Hippel-Lindau Disease (VHL), Wallenberg's syndrome, Werdnig-Hoffinan disease, West syndrome, Whiplash, Williams syndrome, Wilson's disease, Zellweger syndrome.
The present invention can also be employed in detection, diagnosis, treatment, prevention or prognosis of tauopathies (i.e., disorders involving protein tau based pathology), such as, Aging, Alzheimer's disease (familial, sporadic), Amyotrophic lateral sclerosis/Parkinsonism dementia complex of Guam, Argyrophilic grain disease, British type amyloid angiopathy, Corticobasal degeneration, Dementia pugilistica/autism with self injury behaviour, Down's syndrome, Frontotemporal Dementia with Parkinsonism linked to chromosome 17 (FTDP-17), Gerstmann-Straussler-Scheinker disease, Hallenvorden-Spatz disease, Inclusion body myositis, Multisystem atophy, Myotonic dystrophy, Niemann-Pick disease type C, Parkinson with dementia of Guadeloupe, Pick's disease, Presenile dementia with tangles and calcifications, Prion protein cerebral amyloid angiopathy, Progressive supranuclear palsy, Post-encephalitic parkinsonism, Subacute sclerosing panencephalitis, Tangle only dementia.
It i5 also encompassed by the present invention for detection, diagnosis, treatment, prevention or prognosis of psychiatric disorders including Academic Problem, Acculturation Problem, Acute Stress Disorder, Adjustment Disorder Unspecified, Adjustment Disorder With Anxiety, Adjustment Disorder With Depressed Mood, Adjustment Disorder With Disturbance of Conduct, Adjustment Disorder With Mixed Anxiety and Depressed Mood, Adjustment Disorder With Mixed Disturbance of Emotions and Conduct, Adult Antisocial Behavior, Adverse Effects of Medication NOS, Age-Related Cognitive Decline, Agoraphobia Without History of Panic Disorder, Alcohol Abuse, Alcohol Dependence, Alcohol Intoxication, Alcohol Intoxication Delirium, Alcohol Withdrawal, Alcohol Withdrawal Delirium, Alcohol-Induced Anxiety Disorder, Alcohol-Induced Mood Disorder, Alcohol-Induced Persisting Amnestic Disorder, Alcohol-Induced Persisting Dementia, Alcohol-Induced Psychotic Disorder, With Delusions, Alcohol-Induced Psychotic Disorder, With Hallucinations, Alcohol-Induced Sexual Dysfunction, Alcohol-Induced Sleep Disorder, Alcohol-Related Disorder NOS, Amnestic Disorder, Amnestic Disorder NOS, Amphetamine Abuse, Amphetamine Dependence, Amphetamine Intoxication, Amphetamine Intoxication Delirium, Amphetamine Withdrawal, Amphetamine-Induced Anxiety Disorder, Amphetamine-Induced Mood Disorder, Amphetamine-Induced Psychotic Disorder, With Delusions, Amphetamine-Induced Psychotic Disorder, With Hallucinations, Amphetamine-Induced Sexual Dysfunction, Amphetamine-Induced Sleep Disorder, Amphetamine-Related Disorder NOS, Anorexia Nervosa, Antisocial Personality Disorder, Anxiety Disorder, Anxiety Disorder NOS, Asperger's Disorder, Attention-Deficit/Hyperactivity Disorder NOS, Attention-Deficit/Hyperactivity Disorder, Combined Type, Attention-Deficit/Hyperactivity Disorder, Predominantly Hyperactive-Impulsive Type, Attention-Deficit/Hyperactivity Disorder, Predominantly Inattentive Type, Autistic Disorder, Avoidant Personality Disorder, Bereavement, Bipolar Disorder NOS, Bipolar I
Disorder, Most Recent Episode Depressed, In Full Remission, Bipolar I
Disorder, Most Recent Episode Depressed, In Partial Remission, Bipolar I Disorder, Most Recent Episode Depressed, Mild, Bipolar I Disorder, Most Recent Episode Depressed, Moderate, Bipolar I Disorder, Most Recent Episode Depressed, Severe With Psychotic Features, Bipolar I Disorder, Most Recent Episode Depressed, Severe Without Psychotic Features, Bipolar I Disorder, Most Recent Episode Depressed, Unspecified, Bipolar I Disorder, Most Recent Episode Hypomanic, Bipolar I Disorder, Most Recent Episode Manic, In Full Remission, Bipolar I Disorder, Most Recent Episode Manic, In Partial Remission, Bipolar I
Disorder, Most Recent Episode Manic, Mild, Bipolar I Disorder, Most Recent Episode Manic, Moderate, Bipolar I Disorder, Most Recent Episode Manic, Severe With Psychotic Features, Bipolar I Disorder, Most Recent Episode Manic, Severe Without Psychotic Features, Bipolar I Disorder, Most Recent Episode Manic, TJnspecified, Bipolar I Disorder, Most Recent Episode Mixed, In Full Remission, Bipolar I Disorder, Most Recent Episode Mixed, In~Partial Remission, Bipolar I Disorder, Most Recent Episode Mixed, Mild, Bipolar I
Disorder, Most Recent Episode Mixed, Moderate, Bipolar I Disorder, Most Recent Episode Mixed, Severe With Psychotic Features, Bipolar I Disorder, Most Recent Episode Mixed, Severe Without Psychotic Features, Bipolar I Disorder, Most Recent Episode Mixed, Unspecified, Bipolar I Disorder, Most Recent Episode Unspecified, Bipolar I Disorder, Single Manic Episode, In Full Remission, Bipolar I Disorder, Single Manic Episode, In Partial Remission, Bipolar I Disorder, Single Manic Episode, Mild, Bipolar I Disorder, Single Manic Episode, Moderate, Bipolar I Disorder, Single Manic Episode, Severe With Psychotic Features, Bipolar I Disorder, Single Manic Episode, Severe Without Psychotic Features, Bipolar I Disorder, Single Manic Episode, Unspecified, Bipolar II Disorder, Body Dysmorphic Disorder, Borderline Intellectual Functioning, Borderline Personality Disorder, Breathing-Related Sleep Disorder, Brief Psychotic Disorder, Bulimia Nervosa, Caffeine Intoxication, Caffeine-Induced Anxiety Disorder, Caffeine-Induced Sleep Disorder, Caffeine-Related Disorder NOS, Cannabis Abuse, Cannabis Dependence, Cannabis Intoxication, Cannabis Intoxication Delirium, Cannabis-Induced Anxiety Disorder, Cannabis-Induced Psychotic Disorder, With Delusions, Cannabis-Induced Psychotic Disorder, With Hallucinations, Cannabis-Related Disorder NOS, Catatonic Disorder, Child or Adolescent Antisocial Behavior, Childhood Disintegrative Disorder, Chronic Motor or Vocal Tic Disorder, Circadian Rhythm Sleep Disorder, Cocaine Abuse, Cocaine Dependence, Cocaine Intoxication, Cocaine Intoxication Delirium, Cocaine Withdrawal, Cocaine-Induced Anxiety Disorder, Cocaine-Induced Mood Disorder, Cocaine-Induced Psychotic Disorder, With Delusions, Cocaine-Induced Psychotic Disorder, With Hallucinations, Cocaine-Induced Sexual Dysfunction, Cocaine-Induced Sleep Disorder, Cocaine-Related Disorder NOS, Cognitive Disorder NOS, Communication Disorder NOS, Conduct Disorder, Conversion Disorder, Cyclothyrnic Disorder, Delirium Due to[Indicate the General Medical Condition], Delirium NOS, Delusional Disorder, Dementia Due to Creutzfeldt-Jakob Disease, Dementia Due to Head Trauma, Dementia Due to HIV Disease, Dementia Due to Huntington's Disease, Dementia Due to Parkinson's Disease, Dementia Due to Pick's Disease, Dementia Due to[Indicate the General Medical Condition], Dementia NOS, Dementia of the -~
~~
Alzheimer's Type, With Early Onset, Uncomplicated, Dementia of the Alzheimer's Type, With Early Onset, With Delirium, Dementia of the Alzheimer's Type, W ith Early Onset, With Delusions, Dementia of the Alzheimer's Type, With Early Onset, With Depressed Mood, Dementia of the Alzheimer's Type, With Late Onset, Uncomplicated, Dementia of the Alzheimer's Type, With Late Onset, With Delirium, Dementia of the Alzheimer's Type, With Late Onset, With Delusions, Dementia of the Alzheimer's Type, With Late Onset, With Depressed Mood, Dependent Personality Disorder, Depersonalization Disorder, Depressive Disorder NOS, Developmental Coordination Disorder, Diagnosis Deferred on Axis II, Diagnosis or Condition Deferred on Axis I, Disorder of Infancy, Childhood, or Adolescence NOS, Disorder of Written Expression, Disruptive Behavior Disorder NOS, Dissociative Amnesia, Dissociative Disorder NOS, Dissociative Fugue, Dissociative Identity Disorder, Dyspareunia (Not Due to a General Medical Condition), Dyssoxnnia NOS, Dysthymic Disorder, Eating Disorder NOS, Encopresis, With Constipation and Overflow Incontinence, Encopresis, Without Constipation and Overflow Incontinence, Enuresis (Not Due to a General Medical Condition), Exhibitionism, Expressive Language Disorder, Factitious Disorder NOS, Factitious Disorder With Combined Psychological and Physical Signs and Symptoms, Factitious Disorder With Predominantly Physical Signs and Symptoms, Factitious Disorder With Predominantly Psychological Signs and Symptoms, Feeding Disorder of Infancy or Early Childhood, Female Dyspareunia, Female Hypoactive Sexual Desire Disorder, Female Orgasmic Disorder, Female Sexual Arousal Disorder, Fetishism, Frotteurism, Gender Identity Disorder in Adolescents or Adults, Gender Identity Disorder in Children, Gender Identity Disorder NOS, Generalized Anxiety Disorder, Hallucinogen Abuse, Hallucinogen Dependence, Hallucinogen Intoxication, Hallucinogen Intoxication Delirium, Hallucinogen Persisting Perception Disorder, Hallucinogen-Induced Anxiety Disorder, Hallucinogen-Induced Mood Disorder, Hallucinogen-Induced Psychotic Disorder, With Delusions, Hallucinogen-Induced Psychotic Disorder, With Hallucinations, Hallucinogen-Related Disorder NOS, Histrionic Personality Disorder, Hypersomnia, Hypoactive Sexual Desire Disorder, Hypochondriasis, Identity Problem, Impulse-Control Disorder NOS, Inhalant Abuse, Inhalant Dependence, Inhalant Intoxication, Inhalant Intoxication Delirium, Inhalant-Induced Anxiety Disorder, Inhalant-Induced Mood Disorder, Inhalant-Induced Persisting Dementia, Inhalant-Induced Psychotic Disorder, With Delusions, Inhalant-Induced Psychotic Disorder, With Hallucinations, Inhalant-Related Disorder NOS, Insomnia, Intermittent Explosive Disorder, Kleptomania, Learning Disorder NOS, Major Depressive Disorder, Recurrent, In Full Remission, Major Depressive Disorder, Recurrent, In Partial Remission, Major Depressive Disorder, Recurrent, Mild, Major Depressive Disorder, Recurrent, Moderate, Major Depressive Disorder, Recurrent, Severe With Psychotic Features, Major Depressive Disorder, RecurreW, Severe Without Psychotic Features, Major Depressive Disorder, Recurrent, Unspecified, Major Depressive Disorder, Single Episode, In Full Remission, Major Depressive Disorder, Single Episode, In Partial Remission, Major Depressive Disorder, Single Episode, Mild, Major Depressive Disorder, Single Episode, Moderate, Major Depressive Disorder, Single Episode, Severe With Psychotic Features, Major Depressive Disorder, Single Episode, Severe Without Psychotic Features, Major Depressive Disorder, Single Episode, Unspecified, Male Dyspareunia, Male Erectile Disorder, Male Hypoactive Sexual Desire Disorder, Male Orgasmic Disorder, Malingering, Mathematics Disorder, Medication-Induced Movement Disorder NOS, Medication-Induced Postural Tremor, Mental Disorder NOS, Mental Retardation, Severity Unspecified, Mild Mental Retardation, Mixed Receptive-Expressive Language Disorder, Moderate Mental Rztardation, Mood Disorder, Mood Disorder NOS, Narcissistic Personality Disorder, Narcolepsy, Neglect of Child, Neglect of Child (if focus of attention is on victim), Neuroleptic Malignant Syndrome, Neuroleptic-Induced Acute Akathisia, Neuroleptic-Induced Acute Dystonia, Neuroleptic-Induced Parkinsonism, Neuroleptic-Induced Tardive Dyskinesia, Nicotine Dependence, Nicotine Withdrawal, Nicotine-Related Disorder NOS, Nightmare Disorder, No Diagnosis on Axis II, No Diagnosis or Condition on Axis I, Noncompliance With Treatment, Obsessive-Compulsive Disorder, Obsessive-Compulsive Personality Disorder, Occupational Problem, Opioid Abuse, Opioid Dependence, Opioid Intoxication, Opioid Intoxication Delirium, Opioid Withdrawal, Opioid-Induced Mood Disorder, Opioid-Induced Psychotic Disorder, With Delusions, Opioid-Induced Psychotic Disorder, With Hallucinations, Opioid-Induced Sexual Dysfunction, Opioid-Induced Sleep Disorder, Opioid-Related Disorder NOS, Oppositional Defiant Disorder, Other (or Unknown) Substance Abuse, Other (or Unknown) Substance Dependence, Other (or Unknown) Substance Intoxication, Other (or Unknown) Substance Withdrawal, Other (or Unknown) Substance-Induced Anxiety Disorder, Other (or Unknown) Substance-Induced Delirium, Other (or Unknown) Substance-Induced Mood Disorder, Other (or Unknown) Substance-Induced Persisting Amnestic Disorder, Other (or Unknown) Substance-Induced Persisting Dementia, Other (or Unknown) Substance-Induced Psychotic Disorder, With Delusions, Other (or Unknown) Substance-Induced Psychotic Disorder, With Hallucinations, Other (or Unknown) Substance-Induced Sexual Dysfunction, Other (or Unknown) Substance-Induced Sleep Disorder, Other (or Unknown) Substance-Related Disorder NOS, Other Female Sexual Dysfunction, Other Male Sexual Dysfunction, Pain Disorder Associated With Both Psychological Factors and a General Medical Condition, Pain Disorder Associated With Psychological Factors, Panic Disorder With Agoraphobia, Panic Disorder Without Agoraphobia, Paranoid Personality Disorder, Paraphilia NOS, Parasomnia NOS, Parent-Child Relational Problem, Partner Relational Problem, Pathological Gambling, Pedophilia, Personality Change, Personality Disorder NOS, Pervasive Developmental Disorder NOS, Phase of Life Problem, Phencyclidine Abuse, Phencyclidine Dependence, Phencyclidine Intoxication, Phencyclidine Intoxication Delirium, Phencyclidine-Induced Anxiety Disorder, Phencyclidine-Induced Mood Disorder, Phencyclidine-Induced Psychotic Disorder, With Delusions, Phencyclidine-Induced Psychotic Disorder, With Hallucinations, Phencyclidine-Related Disorder NOS, Phonological Disorder, Physical Abuse of Adult, Physical Abuse of Adult (if focus of attention is on victim), Physical Abuse of Child, Physical Abuse of Child (if focus of attention is on victim), Pica, Polysubstance Dependence, Posttraumatic Stress Disorder, Premature Ejaculation, Primary Hypersomnia, Primary Insomnia, Profound Mental Retardation, Psychotic Disorder, With Delusions, Psychotic Disorder, With Hallucinations, Psychotic Disorder NOS, Pyromania, Reactive Attachment Disorder of Infancy or Early Childhood, Reading Disorder, Relational Problem NOS, Relational Problem Related to a Mental Disorder or General Medical Condition, Religious or Spiritual Problem, Rett's Disorder, Ruriliriation Disorder,- Schizoaffective Disorder, Schizoid Personality Disorder, Schizophrenia, Catatonic Type, Schizophrenia, Disorganized Type, Schizophrenia, Paranoid Type, Schizophrenia, Residual Type, Schizophrenia, Undifferentiated Type, Schizophreniform Disorder, Schizotypal Personality Disorder, Sedative, Hypnotic, or Anxiolytic Abuse, Sedative, Hypnotic, or Anxiolytic Dependence, Sedative, Hypnotic, or Anxiolytic Intoxication, Sedative, Hypnotic, or Anxiolytic Intoxication Delirium, Sedative, Hypnotic, or Anxiolytic Withdrawal, Sedative, Hypnotic, or Anxiolytic Withdrawal Delirium, Sedative-, Hypnotic-, or Anxiolytic-Induced Anxiety Disorder, Sedative-, Hypnotic-, or Anxiolytic-Induced Mood Disorder, Sedative-, Hypnotic-, or Anxiolytic-Induced Persisting Amnestic Disorder, Sedative-, Hypnotic-, or Anxiolytic-Induced Persisting Dementia, Sedative-, Hypnotic-, or Anxiolytic-Induced Psychotic Disorder, With Delusions, Sedative-, Hypnotic-, or Anxiolytic-Induced Psychotic Disorder, With Hallucinations, Sedative-, Hypnotic-, or Anxiolytic-Induced Sexual Dysfunction, Sedative-, Hypnotic-, or Anxiolytic-Induced Sleep Disorder, Sedative-, Hypnotic-, or Anxiolytic-Related Disorder NOS, Selective Mutism, Separation Anxiety Disorder, Severe Mental Retardation, Sexual Abuse of Adult, Sexual Abuse of Adult (if focus of attention is on victim), Sexual Abuse of Child, Sexual Abuse of Child (if focus of attention is on victim), Sexual Aversion Disorder, Sexual Disorder NOS, Sexual Dysfunction NOS, Sexual Masochism, Sexual Sadism, Shared Psychotic Disorder, Sibling Relational Problem, Sleep Disorder, Hypersomnia Type, In~.somnia Type, Mixed Type, Parasomnia Type, Sleep Terror Disorder, Sleepwalking Disorder, Social Phobia, Somatization Disorder, Somatoform Disorder NOS, Specific Phobia, Stereotypic Movement Disorder, Stuttering, Tic Disorder NOS, Tourette's Disorder, Transient Tic Disorder, Transvestic Fetishism, Trichotillomania, Undifferentiated Somatoform Disorder, Unspecified Mental Disorder (nonpsychotic), Vaginismus (Not Due to a General Medical Condition), Vascular Dementia, Uncomplicated, Vascular Dementia, With Delirium, Vascular Dementia, With Delusions, Vascular Dementia, With Depressed Mood, Voyeurism.
"Label," "labeled" or "detectable labeled" refers to incorporation of a detectable marker, for example by incorporation of a radioactively labeled compound or attachment to a polypeptide of moieties such as biotin that can be detected by the binding of a section moiety, such as marked avidin. Various methods of labeling polypeptide, nucleic acids, carbohydrates, and other biological or organic molecules are known in the art. Such labels can have a variety of readouts, such as radioactivity, fluorescence, color, chemiluminescence or other readouts known in the art or later developed. The readouts can be based on enzymatic activity, such as beta-galactosidase, beta-lactamase, horseradish peroxidase, alkaline phosphatase, luciferase; radioisotopes such as 3H, 14C, 3sS, iasl or l3il); fluorescent proteins, such as green fluorescent proteins (GFP); or other fluorescent labels, such as FITC, rhodamine, and lanthanides. Where appropriate, these labels can be the product of the expression of reporter genes, as that term is understood in the art. Examples of reporter genes are beta-lactamase (U.S.
Pat. No.

5,741,657 to Tsien et al., issued April 21, 1998) and green fluorescent protein (U.S.
Pat. No. 5,777,079 to Tsien et al., issued July 7, 1998; U.S. Pat. No.
5,804,387 to Cormack et al., issued September 8, 1998).
A "test chemical" or "test compound" or "candidate compound"
refers to a chemical, composition or extract to be tested by at least one method of the present invention to be a putative modulator. A test chemical can be of any chemical composition, such as inorganic, organic or a biomolecule. A
biomolecule can be any molecule of biological origin that is found in or produced at least in part by a cell, and include, but are not limited to polypeptides, nucleic acids, lipids, carbohydrates or combinations thereof. A test chemical is usually not known to bind to the target of interest. "Indentifying a compound" or "screening a drug"
used herein refers to a process to determine the putative modulating or therapeutic function of a candidate compound.
"Control test chemical" or "control compound" refers to a chemical known to bind to the target (for example, a known agonist, antagonist, partial agonist or inverse agonist). Test chemical does not typically include a chemical added to a mixture as a control condition that alters the function of the target to determine signal specificity in an assay. Such control chemicals or conditions include chemicals that (1) non-specifically or substantially disrupt protein structure (for example denaturing agents such as urea or guandium, sulfhydryl reagents such as dithiotritol and beta-mercaptoethanol), (2) generally inhibit cell metabolism (for example mitochondria) uncouples) and (3) non-specifically disrupt electrostatic or hydrophobic interactions of a protein (for example, high salt concentrations or detergents at concentrations sufficient to non-specifically disrupt hydrophobic or electrostatic interactions). The term "test chemical" or "candidate compound"
also does not typically include chemicals known to be unsuitable for a therapeutic use for a particular indication due to toxicity of the subject. Usually, various predetermined concentrations of test chemicals axe used for determining their activity. ! If the molecular weight of a test chemical is known, the following ranges of concentrations can be used: between about 0.001 micromolar and about 10 millimolar, preferably between about 0.01 micromolar and about 1 millimolar, more preferably between about 0.1 micromolar and about 100 micromolar. When extracts are uses a test chemicals, the concentration of test chemical used can be expressed on a weight to volume basis. Under these circumstances, the following ranges of concentrations can be used: between about 0.001 micrograms/ml and about 1 milligram/ml, preferably between about 0.01 micrograms/ml and about 100 micrograms/ml, and more preferably between about 0.1 micrograms/ml and about 10 micrograms/ml.
"Macromolecule" refers to a molecule with a molecular mass greater than a one thousand daltons, such as a protein, nucleic acid, or polysaccharide.
"Treating" or "treatment" as used herein means to ameliorate, suppress, mitigate or eliminate the clinical symptoms after the onset (i.e., clinical manifestation) of a disease state, such as an AD, including, but not limited to inhibiting neuronal degeneration or neuronal death, promoting or stimulating neuronal growth such that the symptoms of the disease condition are prevented or alleviated. Such treatment can include chemicals, such as chemotherapeutic agents or test compounds and/or non-chemical treatment, such as electrical pules (such as electroinnovation), magnetic fields or radiation (such as radiation therapy) (see, for example, Buonanno et al., Nucleic Acids Res. 20:539-544 (1992)). An effective or successful treatment provides a clinically observable improvement.
By "candidate treatment process" is meant administration of a candidate compound to a subject, or modification of environment, diet, behavior of the subject. By "control treatment process" is meant that the nature status or state of a subject being maintained without any treating or modification, or a treatment process having known references or properties is performed.
By "prevent", "preventing" or "prevention' is meant that chances of regaining and/or worsening and/or progression of the symptoms of a neurological diseases, such as, for example, AD, are lowered, reduced or eliminated after the symptoms are ameliorated, suppressed, mitigated or eliminated by the treatment.
A "specific binding member" refers to a member of a group of two or more moieties that can specifically bind with each other rather than becoming non, specifically associated with each other, such as by precipitation. Examples of specific binding members include, but are not limited to, antigen-antibody, receptor-ligand and nucleic acid-nucleic acid pairs.
"Specific," "specifically," "specifically bind" or a "specific binding"
in the context of the binding of first specific binding member with at least one other specific binding member refers to binding that is preferential and not non-specific.
Preferably, a specific binding reaction is unique for the specific binding members, but that need not be the case.
"Detectably bind" or "detectable binding" refers to the specific binding of one specific binding member with at least one other specific binding member that can be detected. For example, one specific binding member can be detectably labeled such that the detectable presence of the label indicates a specific binding event. The detection limits of such detectable binding are related to the detectable label used and the detection method or device used.
An "antibody" refers to an immunoglobulin of any class or subclass, a portion thereof or an active fragment thereof, wherein an active fragment of an antibody retains its specific binding capability. An antibody can be a polyclonal axitibody, a monoclonal antibody or a mixture thereof.
By "probe" is meant a substance, preferably a biomolecule, such as a fragment of DNA sequence or an antibody, which is labeled or otherwise marked and used to detect or identify another substance in a sample. An example of a probe can be a biomolecule that is labeled with radioactive isotopes or with a fluorescent marker that selectively binds to a specific gene so it can be isolated or identified or a strand of nucleic acid which can be labeled and used to hybridize to a _ . .. _ . . complementary molecule from a mixture of other nucleic acids. The term "probe" _ _ _ _ W , .
used herein can be also referred to a single-stranded nucleic acid molecule with a known nucleotide sequence which is labeled in some way (for example, radioactively, fluorescently, or immunologically) and used to find and mark certain DNA or RNA sequences of interest to a researcher by hybridizing to it. A
specific example of the probe used in the present invention is anti-aPKC antiserum.
A "specific probe" such as used in "aPKC specifc probe" is refered to any probe that specifically binds to aPKC gene or gene product(s). Preferably, such specific binding is a detectable binding.
A "tissue" refers to a collection of cells as known in the art. A
"culture" of cells is a collection of cells as known in the art and can be a clonal population of cells or a mixed population of cells. A "tumor tissue" is a collection of cells that includes at least one cell derived from at least one tumor.
A "tissue extract" refers to a preparation that is derived from at least one source of tissue that has been treated such that the tissue and/or at least one cellular component of the cells in the tissue is no longer in its natural state or environment. For example, a tissue extract can be made by rupturing tissue using methods known in the art.
A "sample" includes any physical sample that includes a cell or a cell extract from a cell, a tissue, a biopsy sample, a tissue extract, for example.
A sample can be from a biological source such as a subject or animal or a portion thereof, or from a cell culture. Samples from a biological source can be from a normal or abnormal organism (such as an organism suffering from a condition or disease state, such as a neoplasm) or portion thereof and can be from any fluid, tissue or organ, including healthy or abnormal (such as diseased or neoplastic) fluids, tissues or organs. Samples from a subject or animal can be used in the present invention as obtained from the subject or animal, processed such as by sectioning, aspiration such as for bone marrow specimens or cultured such that cells from the sample can be sustained in vitro as a primary or continuous cell culture or cell line. For example, a sample in the present invention can be a tissue biopsy, cerebrospinal fluid (CSF), or a body fluid, such as blood, sample. In particular, a "tumor sample" is a sample that includes at least one cell derived from at least one tumor.
"Diagnosing" or "diagnosis" refers to the determination of whether a subject comprises a disease or condition, such as a nervous system~disorder or cancer. "Diagnosing" also refers to distinguishing one cancer from another.
By "prognosing" or "prognosis" is meant the determination or prediction of the course of a disease or condition, such as cancer. The course of a disease or condition can be prognosed, for example, based on life expectancy or quality of life. Prognosing includes the determination of the time course of a disease or condition, with or without a treatment or treatments. In the instance where treatments) are contemplated, the prognosing includes prognosing the efficacy of a treatment for a disease or condition, such as cancer, or prognosing a malignancy.
A "control sample" refers to a sample that acts as a positive or negative control as they are known in the art and as appropriate for a particular assay. A control can be performed contemporaneously with an assay or be performed at a prior or later time. The results of an assay can be compared to a control to determine the validity of the assay. Controls can also be used to produce standard curves such that the results of an assay can be semi-quantitative or quantitative in nature. A reference range, i.e., a known range of normal values, can also be used as a control.
By "reference DNA" or "reference DNA sequence" is meant a DNA
sequence, where its sequence is known and normal, i.e., without any mutation, and where it encompasses the same region in the genome of a species as a DNA
molecule to be compared, assayed or analyzed.
By "promoter" or "promoter region" is meant a nucleic acid sequence that controls expression of a coding sequence or a gene of interest. By "control expresion" is meant controlling production of RNA (e.g., mRNA or non-coding transcripts) by providing the recognition site for RNA polymerase and/or other factors necessary for starting transcription at the correct site. A promoter or promoter region usually resides upstream (5') of a coding sequence. As contemplated by the present invention, a promoter or promoter region can include variations of promoters derived by means of ligation to various regulatory sequences, random or controlled mutagenesis, and addition or duplication of enhancersequences.
By "transgene" is meant any nucleic acid sequence non-native to a _ ._..
cell or an organism into which the nucleic acid sequence is transformed.
"Transgene" also encompasses the component parts of a native gene of an organism modified by insertion of a non-native nucleic acid sequence by directed recombination.
The present invention is directed to the identification of the amount, localization and activity of atypical isoforms of protein kinase C (aPKC), e.g.
PKM~, and their role in disorders of the nervous system, such as Alzheimer's disease (AD).
Accordingly, one embodiment of the present invention is directed to diagnosis of AD. According to the present invention, a method for diagnosing neurological dysfunctions or nervous system disorders in a subject, using an aPKC
specific probe, is provided. The diagnostic method of the present invention includes the steps of a. contacting a sample from the subject, e.g. a tissue biopsy, cerebrospinal fluid (CSF), or a blood sample, with an aPKC
specific probe, b. detecting the binding of the probe to the sample to determine the amount, localization or activity of the aPKC in the sample, c. contacting a control sample with the aPKC specific probe, d. detecting the binding of the probe to the control sample, e.g. a tissue biopsy, CSF, or a blood sample, to determine the amount, localization or activity of the aPKC in the control sample, and e. comparing the amount, localization or activity of the aPKC in Step b with the amount, localization or activity of the aPKC in Step d, whereby if the amount, localization or activity of the aPKC in Step b is different from the amount, localization or activity of the aPKC in Step d, a nervous system disorder in the subject is present.
In accordance with the present invention, using probes to aPKC
isoforms in the form of antibodies or nucleic acid, one can detect changes of aPKC
in tissues from a subject through conventional techniques (Maniatis et al., J.
Molecular Cloning, a laboratory manual, 1987; Ausubel, F.M., Cu~~~ent Protocols iia Molecular Biology, 1987), and thereby ascertain whether an individual has a neurological disease, such as AD, or is likely to develop one. These probes can be used on postmortem autopsy tissue, brain biopsy tissue or any other tissue, tissue extract or body fluid (e.g., blood). In accordance with the present invention, a preferred probe is the antisense probe described in Example 11. Also in accordance with the present invention, using gene analysis for mutations in the aPKCs, one can detect changes of aPKC in tissues from a subject through conventional techniques (Ausubel, F.M., Cu~reut Protocols iu Molecular Biology, 1987), and thereby ascertain whether an individual has a neurological disease or is likely to develop one.
Thus, it is an object of the present invention to detect neurological disorders, such as AD, at an early stage in order to treat and/or prevent the disorder.
Another embodiment of the present invention is directed to a method for screening drugs or molecular compounds useful for modulating the amount or activity of the aPKC. According to the present invention, a method for screening molecular compounds, e.g. peptides and small molecules, using cells and aPKC
specific probes is provided. Such method includes:
a. providing cells wherein aPKC gene is expressed, b. incubating the cells with a candidate compound for a sufficient time to induce a change in the amount, localization or activity of aPKC in the cells, c. incubating the cells as in Step b, in the absence of the candidate compound, d. contacting the cells from Step b and Step c with an equal amount of an aPKC-specific probe, e. detecting the binding of the probe to the cells to determine the amount, localization or activity of the aPKC in the cell from Step b and Step c, and f. comparing the amount, localization or activity of the aPKC in the cells, wherein if the amount, localization or activity of the aPKC
in the cells from Step b is different from the amount, localization or activity of the aPKC in the cells from Step c, the candidate compound is identified as a compound that modulates aPKC.
An alternate method for screening molecular compounds for use in treatment of brain disorders involves the over-expression or deletion of genetic elements containing atypical PKC sequences in cells or animals, e.g. mice, and assaying said cells or animals for atypical PKC activity or levels.
In accordance with present invention, the aPKC isoforms are used as rational targets for drug design for the purpose of treating and/or preventing AD and other neurological disorders. There are numerous methods currently available for testing the ability of drugs to influence the activity of proteins (Enna, S.
J., Current Protocols in Pharmacology, 1998). The present invention is directed to the discovery that aPKC plays a key role in neurological disease and that changes in aPKC can be used to screen for useful drugs.
According to the present invention, a preferred compound is chelerythrine chloride (a PKC inhibitor), the zeta-inhibitory peptide (ZIl'), or a selective aPKC inhibitor. An example of ZIP is myristoylated PKC~
pseudosubstrate peptide, i.e., Myr-SIYRRGARRWRKLY (SEQ ID NO: 10). See, Standaert et al., 1999, J. Biol. Chem. 274(20):14074-78.
According to the present invention, drugs that modulate aPKC can be screened by employing methodologies and related reagents that are known to the persons skilled in the art. Three such conventional methodologies have been developed, in both iyr vivo and i~c vitro systems. The first is a kinase assay using recombinant expressed PKM~ in a baculovirus system. The second is a cell culture system using immunofluorescence. The third is using recombinant aPKC
transfected into cultured cells. See, Ausubel, F.M., Cu~f-ent Protocols ih Molecular Biology, 1987.
In accordance with the present invention, an aPKC, including PKM~, contains a non-conventional ATP binding site motif GXGXXA (SEQ ID NO: 8), wherein G is amino acid glycine, X is any amino acid. This special characteristic of aPKC makes it less likely that drugs targeting these molecules will have harmful side effects comparing to other kinases or other PKC isoforms, which have ATP
binding site hallmark motif GXGXXG (SEQ ID NO: 9).
In a particular embodiment of the present invention, an in vitro cell-free method for screening drugs or molecular compounds useful for modulating the amount, localization or activity of the aPKC, using aPKC and.a substrate, is "_._ _ : "_ _ ,_ provided. Such method includes:
a. incubating an aPKC in a first container with adenosine triphosphate (ATP), preferably radioactively labeled ATP, a substrate of the aPKC, e.g. protein tau, with a candidate compound, for a sufficient time to induce a change in the amount or activity of the aPKC in said first containner, b. incubating the aPKC in a second container with ATP, preferably radioactively labeled ATP, and the substrate of said aPKC, e.g.
protein tau, for a sufficient time to induce a change in the amount or activity of aPKC in said second container, c. quantifying the amount of incorporation of the phosphate into the substrate in the first container and the second container, and d. comparing the amount of incorporation in the first container and the second container, whereby a difference in the amount of incorporation in the first container and the second container is indicative that the candidate compound is identified as a compound modulating aPKC amount, localization or activity.
A variation of this method involves using a phospho-specific antisera to quantify phosphate incorporation into the substrate.

Still another embodiment of the present invention is directed to a method, including gene therapy, for treating and/or preventing neurological disorders. According to the present invention, a method for treating and/or preventing neurological dysfunction is provided which employs a sequence corresponding to an aPKC, e.g. PKM~ (or an antisense sequence of aPKC) and an expression vector. This method includes the steps of a. inserting the aPKC sequence, e.g. PKM~, into the expression vector, and b. administering the vector to a subject, e.g. a patient, whereby the vector treats and/or prevents a neurological dysfunction.
The methods of the present invention can be employed in the treatment and/or prevention of a variety of neurological disorders characterized by abnormal aPKC activity, such as phosphorylation of protein tau and co-localization 4 with NFT. Such tau-associated filamentous aggregates are rieuropathological hallmarks of Alzheimer's disease (AD), Pick's disease (PiD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD), Parkinson's Disease (PD), for example.
According to the present invention, aPKC function is altered in AD
and other neurological disorders. Thus, in accordance with the present invention, aPKC and mutated forms, e.g. inactivated form of kinase, can be introduced to treat and/or prevent AD and other neurological disorders. Using gene therapy, the aPKC
cDNA, preferably PKM~ cDNA, sequences or the mutated aPKC sequences, can be introduced to treat these diseases.
Such sequences are preferably provided in an expression vector.
Expression vectors for use in the present methods include any appropriate gene therapy vectors, such as nonviral (e.g., plasmid vectors), retroviral, adenoviral, herpes simplex viral, adeno-associated viral, polio viruses and vaccinia vectors.
Examples of retroviral vectors include, but are not limited to, Moloney murine leukemia virus (MoMuLV), Harvey murine sarcoma virus (HaMuSV), murine mammary tumor virus (MuMTV), and Rous Sarcoma Virus (RSV)-derived recombinant vectors. Multiple teachings of gene therapy are available to those skilled in the art (Anderson, W. F., Science, 288: 627-629, 20001; Anderson, W. F., Scieyace, 226: 401-409, 1984; Anderson, W. F., Scieyace, 256: 808-813, 1993;

Friedmann, T., Science, 244: 1275-1281, 1989). Preferred vectors include neurotropic vectors such as herpes simplex viral vectors (U.S. Patent No.
5,673,344 to Kelly et al.) and adenoviral vectors (Barkats et al., Prog Neurobiol, 55:
333-341, 1998).
In a further embodiment, present invention provides antibodies against PKM~ for detection, treatment and/or prevention of neurological disorders, e.g. AD.
The present invention further provides antibodies against PKM~ for detection, treatment and/or prevention of neurological disorders, e.g. AD.
Those skilled in the art can use any of the well-known techniques and commercially available resources to generate such monoclonal or polyclonal antibodies (Harlow et al., Using Antibodies: A Laboratory Manual, 1999). Once an antibody is obtained, . - such antibody can be tested in assays to determine whether such antibody e~ibits - -specific activity.
A still further embodiment of the present invention provides a method for constructing transgenic animals, such as a knock-out mouse lacking aPKC or a mouse that overexpresses the wild type or a mutant aPKC, that are useful as animal models of neurological dysfunction. The method includes:
a. constructing a transgenic animal having an altered aPKC amount, localization or activity, e.g., by deleting an aPKC gene in the animal using knock-out techniques known to one skilled in the b. treating the transgenic animal from Step a with a candidate treatment process, c. treating the transgenic animal from Step a with a control treatment process, r d. assaying the transgenic animals from Steps b and c for a biochemical or behavioral change, and e. comparing the results of the assay of the transgenic animals from Steps b and Step c, wherein a difference is indicative the efficacy of the candidate treatment process in alleviating the neurological dysfunction.

A variation of the method involves over-expression of either wild-type or mutated aPKC in a transgenic animal, alone or in combination with one or more other transgenes expressing mutations or polymorphisms in genes associated with neurodegeneration, e.g. superoxide dismutase, tau, (3-amyloid, a-synuclein, and apolipoprotein E.
A yet further embodiment of the present invention is directed to the genetic screening of DNA for mutations or polyrnorphisms in the DNA sequence of the aPKC genes, e.g. PKC~I/II and PKCL/~,, and regions regulating the expression of these genes including promoter regions, enhancer regions and negative regulatory regions. A method for such screening includes:
a. isolating DNA from a sample of a subject, b. sequencing an aPKC gene or its regulating region of the DNA
from Step a and, c. comparing the DNA sequence from Step b to a reference DNA
sequence, wherein the reference DNA is a known normal DNA
sequence of the same region as sequenced DNA in Step b but without any mutation, whereby a difference between the DNA
sequence from Step b and the reference sequence is indicative of genetic susceptibility to a neurological or psychiatric disorder.
A particular embodiment of the present invention is directed to the use of a known aPKC interacting protein for all of the above methods.
The present invention is also directed toward the diagnosis and treatment of other abnormal protein aggregates including oc-synuclein seen in PD, multisystem atrophy (MSA) and dementia with Lewy bodies (DLB) and (3-amyloid in AD and normal aging.
According to the present invention, abnormal aggregation of aPKC
protein, such as PKCv/7~ (one of the two members of aPKC) protein, can cause neurodegenerative disorders. It is a discovery of the present invention that PKCv/~, protein distribute in a variety of tauopathies and a-synucleinopathies.
Specifically, using immunocytochemistry, the present invention demonstrates that an anti-PKCv/~, antibody can label tau-positive structures in Alzheimer's disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and Pick's disease (PiD); a,-synuclein-positive Lewy bodies in idiopathic Parkinson's disease and dementia with Lewy bodies, and glial inclusions in mufti-system atrophy; ocB-crystalline-containing ballooned neurons in CBD and PiD; and actin-rich Hirano bodies in AD, PiD and elderly individuals. See Example 12.
Still another emobidment of the present invention provides methods for diagnosing various forms of cancer, such as neuroblastoma, oligodendroglioma, meningioma, lymphoma (myeloma), leukemia (including acute myelocytic leukemia (AML)), melanoma, squamous cell carcinoma, hepatocellular carcinoma, parathyroid tumors, pheochromocytoma, paraganglioma, intravascular lymphomatosis, breast cancer, liver cancer, lung cancer, prostate cancer, bladder cancer, ovarian cancer, endometrial cancer, head and neck cancer and gastrointestinal cancers including colorectal cancer and pancreatic cancer.
According to the present invention, a method for diagnosing and/or staging a tumor is provided. The diagnostic method of the invention includes the-steps of a. contacting a tumor sample, e. g. a human biopsy sample, from a subject, with an aPKC specific probe, preferably a PKC~ specific probe, b. detecting the binding of the probe to the tumor sample to quantify the level, amount or activity of said aPKC in said tumor sample, c. contacting a control sample with the aPKC specific probe, d. detecting the binding of the probe to the control sample to quantify the level, amount or activity of the aPKC in the control sample, and e. comparing the level, amount or activity of the aPKC in Step b with the level, amount or activity of the aPKC in Step d, wherein the difference of the level, amount or activity of the aPKC is indicative of the type and the staging of the tumor.
Another embodiment of the invention provides methods for drug screening for the purpose of treating and/or preventing cancer, e. g.
neuroblastoma.
According to the present invention, a method for screening molecular compounds, e.
g. peptides and small molecules, is provided.
Still another embodiment of the invention provides methods for , treating cancer with gene therapy.

According to the present invention, the therapeutic compositions provided herein, such as expression vectors or antibodies, can be administered to the subject being treated by standard routes, including, but not limited to, the oral, ophthalmic, nasal, topical, transdermal, parenteral (e.g., intravenous, intraperitoneal, intradermal, subcutaneous or intramuscular), intracranial, intracerebral, intraspinal, intravaginal, intrauterine, or rectal route. Depending on the condition being treated, one route may be preferred over others, which can be determined by those skilled in the art. For example, the topical or dermal route can be chosen when the target area includes tissues or organs readily accessible by topical application, such as neurological conditions of the eye or the facial tissue. For certain conditions, direct injection or surgical implantation in the proximity of the damaged tissues or cells is preferred in order to avoid the problems presented by the blood-brain barrier.
Successful delivery to the central nervous system (CNS) by direct injection or implantation has been documented (Otto et al., J Neurosci Res, 22: 83-91, 1989;
Goodman et al., Goodman ~ Gilman's the Pharmacological Basis of Therapeutics, 2001; Williams et al., Proc Natl Acad Sci USA, 83: 9231-35, 1986).
According to the present invention, the therapeutic ingredients are preferably administered to the subject in need thereof as early as possible, e.g., after the neuronal injury or neuronal death caused by NFT, or any other nervous system disorder or cancer occurs, in order to achieve the best therapeutic efficacy.
The amount administered varies among patients and by route administered but should be sufficient enough to achieve a concentration to treat or prevent the disease or disorder or is sufficient to maintain said aPKC activity at a normal level. By "normal level" is meant that the level a biomolecule or compound functions or , occurrs in a natural way; lacks observable or scientifically detectable abnormalities or deficiencies. For example, normal level aPKC in a human body or an organ or tissue thereof is from about 0.005% to about 0.05% of total protein in the human body or an organ or tissue thereof, preferably, the organ is a human brain. In a particular embodiment of the present invention, ZIP or chelerythrine can be administered between about 100 nM and about 10 ~,M of in a desired tissue.
The present invention is further illustrated by the following non-limiting example. This example is included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the example represents techniques discovered by the inventors to function well in the practice of the invention. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention, therefore all matter set forth or shown in the accompanying drawings is to be interpreted as illustrative and not in a limiting sense. All references cited herein are hereby expressly incorporated-herein by reference.

Example 1 Production of PKC isozyme antisera Peptides used as immunogens were synthesized by Quality Controlled Biochemicals (Hopkinton, MA) and corresponded to the amino-terminal (~-N1, TDPKMDRSGGRVRLKC, SEQ ID NO: 1), catalytic-domain (~-C2, TLPPFQPQITDDYGLC, SEQ ID NO: 2) or carboxyl-terminal (~-C1, EYINPLLLSAEESV, SEQ ID NO: 3) of PKC~. In addition, a terminal cysteine residue was added to each of the sequences for coupling purposes. The peptides were coupled to maleimide-activated bovine serum albumin (BSA, Pierce, Rockford, IL), according to the manufacturer's instructions. Peptide conjugates were mixed with Titermax (CytRx Corp., Norcross, GA) and injected intramuscularly into female New Zealand rabbits, one to three weeks of age.
After three boosts at four-week intervals, the antisera were affinity-purified on Sulpholink gel columns (Pierce, Rockford, IL), to which the immunizing peptide had been conjugated according to the manufacturer's instructions. The antiserum to v/~, is a mouse monoclonal antibody prepared against the v/7~ catalytic domain (Transduction Laboratories, Lexington, KY).

Example 2 Western blot of AD brain Fresh frozen tissue from autopsy brain tissue derived from 4 neuropathologically confirmed cases of AD and 3 controls from individuals without neurological disease were homogenized in buffer containing protease inhibitors (50 mM HEPES, pH 7.5, S mM EDTA, 5 mM EGTA, 5 mM 2-mercaptoethanol, 0.1 mM phenylmethylsulfonyl fluoride, aprotinin (17 kallikrein units/ml), 5 mM
benzamidine, 0.1 mM leupeptin) and phosphatase inhibitors (50 mM NaF, 40 mM (3-glycerol phosphate, 10 mM pyrophosphate). Protein concentration was measured by Pierce assay. Sample buffer was added and samples boiled for 10 min. 15 ~,g of total protein was subjected to SDS-PAGE, transferred to nitrocellulose, and probed with specific anti-PKC~ and anti-PKCL/7~ antibodies, and visualized by enhanced chemiluminescence (Amersham Biosciences, Freiburg, Germany).

Example 3 Pathological stains Eight micron sections were cut from paraffin embedded tissue. All tissue was deparaffinized and rehydrated prior to use. For hematoxylin and eosin staining, sections were incubated in Gills hematoxylin for 5 minutes, rinsed in water, two changes, then dipped in bluing solution ten times and rinsed again. Next, sections were incubated in eosin Y for 4 minutes, dehydrated and coversliped.
For Sevier-Munger silver staining, slides were incubated in 60 °C silver nitrate solution (20%) for 15 min. Slides were rinsed and placed in a clean dry staining jar.
Slides were then developed in ammoniacal silver solution for 5 to 30 minutes.
Sections were then rinsed 3 changes of water and incubated in 5% sodium thiosulfate for minutes. Last, slides were washed with water, dehydrated, and cover-slipped.

Example 4 Antigen retrieval For antigen retrieval, deparaffinized and rehydrated slides were submerged in 10 mM citrate buffer (pH 6.0) and microwaved for 5 minutes.
Slides were then transferred to a second container with heated distilled water and allowed to cool. Slides were then rinsed in PBS for 5 minutes. Some slides were treated with formic acid for 3 minutes prior to citrate treatment.

Example 5 Immunohistochemical staining Slides were treated with 3% hydrogen peroxide for 10 minutes, rinsed in PBS for 5 minutes, and blocked in 4% normal horse serum for 20 minutes.
Tissue was then incubated in primary antibody in a humidity chamber overnight on a rotator plate. The following day, slides were rinsed in two changes of PBS for minutes each and incubated in biotinylated secondary (1:200) for 30 min.
Slides were then rinsed again in two changes of PBS for 5 minutes each then incubated in R.T.U. ABC reagent (Vector Laboratories) for 30 minutes, and rinsed again in two changes of PBS for 5 minutes each. Tissue was then developed in DAB solution, rinsed in tap water and counterstained with hematoxylin, dehydrated and coverslipped.

Example 6 PKM~ protein is present in human brain Western blot on homogenates of human brain samples were conducted to confirm antisera specificity and document PKM~ protein in humans (Fig. 3). Fresh frozen tissue was obtained from the Rush Alzheimer's Disease Center (Chicago, Illinois) (Table 1 ). The average PMI for the AD (4.75 h) and control (4.00 h) cases was the same. The average age for the AD (69.5 yr) cases was less than controls (86.7 yr). The diagnosis was confirmed pathologically for all patients.
Table 1:
Summary of patient data (Western blot) Case PMI (hours)Age Sex Reagan Index Braak Stage _ _ . - Low likelihood ___.___ _.__ of Low likelihood of Low likelihood of High likelihood of 4 4.5 78 M AD V/VI

High likelihood of 5 5.5 62 F AD V/VI

High likelihood of 6 4, 5 64 F AD V/VI

High likelihood of 7 4.5 74 M AD V/VI

The PKCi antibody showed one band at ~79 k.D in all regions tested.
A faint, minor band at ~50 kD was seen suggesting the presence of a small amount of PKMt. The C-terminal antibody, ~-C1, which detects both atypical forms, detected three bands at ~55, ~79 and 160 kD. These bands represent aPKM, aPKC

and an unidentified band respectively. The aPKC band was strongest in the cerebellum and weak in all other regions. The ~ specific antibody, ~-C2, which does not cross-react with t but reacts with both PKC~ and PKM~ detected major bands at ~55 kD and ~79 kD, and a minor band at ~60 kD. The ~79 kD band is PKC~ and was only present iii the cerebellum. The 55 kD and 60 kD bands were seen in all regions tested. The N-terminal antibody, ~-Nl, which reacts only with ~ forms with a regulatory domain showed one strong unidentified band at ~45 kD. There were no PKM or PKC forms seen with this antibody.

Example 7 PKCy and PKCiI~,. but not PKM ~ decrease in the superior temporal cortex in AD
To determine whether there are changes in the levels of aPKC, densitometric analysis of Western blots was done on total protein homogenates prepared from the superior temporal cortex derived from AD (n=4) and controls (n=3). PKCy was included for comparison. PKCy was significantly lower (p =
0.031) in the AD samples (0.30 ~ 0.07) than controls (0.79 ~ 0.34) representing a 63% decrease. There was a smaller, but statistically significant decrease in PKCv (la = 0.006) in AD (0.86 ~ 0.08) versus controls (1.15 ~ 0.08) representing a 25%
decrease. In contrast, PKM~ was not significantly different in AD (0.69 ~
0.39) versus controls (0.63 ~ 0.22). See, Figure 4.

Example 8 PKCi/~,. but not PKM~ nor PKCy increase in the caudate nucleus in AD
For comparison, Western blots were conducted on the caudate nucleus. PKCy was not significantly changed in the AD samples (1.44 ~
0.15) as compared to controls (1.24 ~ 0.10). There was a smaller, but statistically significant decrease in PKCt (p = 0.006) in AD (0.86 ~ 0.08) versus controls (1.15 ~ 0.08) representing a 25% decrease. In contrast, PKM~ was not significantly different in AD (0.69 ~ 0.39) versus controls (0.63 ~ 0.22). See Figure 5.

Example 9 Localization of aPKC in human brain To localize aPKC in human brain, immunohistochemistry was done on paraffin-embedded sections from control cases (n=2).
Table 2:
Summary of patient data (immunohistochemistry) Case PMI Age Sex Dx 1 4.5 82 F AD

2 6.5 86 F AD

3 4.0 72 F AD

4 ~ Na 60 F AD

Na 83 F AD

6 Na 98 M Braak Stage II

7 12 _ 47 . _. F _ _ _ ._ control _ ~ . .. . ..

Staining with ~-C 1 was evident in the perikarya of pyramidal cells, extending into proximal dendrites (Fig. 6B). There was no neuronal nuclear staining.
Staining was also observed in glia. The cytoplasm and nuclei of astrocytes in hippocampal area CA-4 stained strongly with ~-C1 indicating the presence of aPKC (Fig. 7B). PKCv/~, immunoreactivity in astrocytes was also observed in cortex (Fig. 7A). ~-C2 did not stain astrocytes.
Ependymal cells also stained with ~-C1 (Fig. 8). Similar results were seen with ~-C2 and t/~,, indicating the presence of both ~ and v/7~ forms in this cell type.

Example 10 PKM ~ colocalizes with neurofibrillary tangles and Hirano bodies To examine changes in the distribution of aPKC in AD, sections of hippocampus from patients (n=4) with neuropathologically confirmed AD were stained with aPKC antibodies. Despite high staining in the neuropil, there was minimal v/7~ immunoreactivity in NFTs (Fig. 9, top right). In contrast, both ~-Cl and ~-C2 strongly reacted with NFTs (Fig. 9, middle right and left). Silver stain confirms the presence of SPs and NFTs in this region. Neuropil threads, dystrophic neurites and SPs failed to label. Since neuropil threads and dystrophic neurites both contain PHFs, sections were pre-treated with citrate and formic acid to unmask the _ -. epitopes. hnmunoreactivity in distrophic neurites and neuropil threads was een after unmasking when stained with ~-C1 (Fig. 10). Silver stain from a non-adjacent section in the same region confirmed the presence of SPs.
Strong staining was seen in HB with ~-C1, ~-C2 and v/~,. On H&E, the presence of HB was confirmed. See Figure 11.

Example 11 The distribution of PKM~ cor relates with that of a unique brain RNA
encoding an independent ~ catalytic domain One explanation for the abundance of PKM~ in forebrain despite very low levels of PKC~ is that PKM~ is not a proteolytic product of PKC~. The ~
gene produces two sets of RNAs: full-length PKC~ mRNA and an RNA referred to as ~' (Figure 12A). The 3' end of ~' RNA consists of sequence for a partial ~
regulatory domain and its complete hinge and catalytic domain, which are identical to that in PKC~
mRNA (Figure 12A). The 5' end of ~' RNA, however, is unique sequence that lacks an AUG to initiate translation of the ~ regulatory domain. The first AUG for an open reading frame (ORF) of the ~ sequence begins in its hinge (Figure 12A).
Therefore, the _ . _ ~', RNA can expres_s_PKM~._ To. determine whether the distributions of the ~ RNAs correlate with the different ~ proteins, the expression of PKC~ mRNA and ~' was analyzed by RT-PCR, RNase protection, and Northern blot analysis (Figures 12A-12C).
For reverse-transcription polymerise chain reaction (RT-PCR), total RNA isolated from rat tissue was used to synthesize cDNA with the Superscript Preimplification System for First Strand cDNA Synthesis Kit (Gibco Invitrogen, Grand Island, NY). 200 ng of cDNA was used in 100 ~.1 final volume PCR reactions.
Amplified was for 34 cycles with 94 °C for 30 sec, 60 °C for 1 minutes, and' 72 °C for 1 minutes as cycle parameters, with a final step of 72 °C for 10 minutes.
For amplification of PKC~ and PKM~ cDNAs, specific forward primers were F 5'-CCATGCCCAGCAGGACCACC-3' (SEQ ID NO: 12) and F 5'-CCTTCTATTAGATGCCTGCTCTCC-3' (SEQ ID NO: 13), respectively, and R 5'-TGAAGGAAGGTCTACACCATCGTTC-3' (SEQ ID NO: 14), was the reverse primer for both. As a control we used GAPDH primers, F 5'-ACATGGTCTACATGTTCC-3' (SEQ ID NO: 15) and R 5'-CAGATCCACAACGGAATAC-3' (SEQ ID NO: 16).
Using specific forward primers that distinguish between the two ~ RNAs, RT-PCR analysis showed abundant expression of ~' in brain, but not in non-neural tissues (Figure 12A), in accordance with the distribution of PKM~. Only with a higher number of PCR cycles could a small amount of ~' RNA be detected in kidney (data not shown). In contrast, FKC~ mRNA was expressed in kidney, lung, testis, and cerebellum, but not in neocortex or hippocampus (Figure 12A). This distribution correlates with the expression of PKC~.
These findings by RNase protection were quantified using an antisense probe that protects a 345 nucleotide fragment of PKC~ mRNA and a 202 nucleotide fragment of ~' RNA (Figure 12B). Confirming the RT-PCR, the RNase protection product of ~' RNA was found only in brain, whereas the protection product of the PKC~
mRNA was observed in kidney, lung, testis, and cerebellum, but not in neocortex or hippocampus (Figure 12B). The relative levels of PKC~ mRNA and ~' RNA were examined by comparing them to mRNA for the housekeeping rat acidic ribosomal protein (RARP, Figure 12B, center and bottom). The expression of ~' RNA in brain was higher than that of PKC~ mRNA in any of the tissues examined.
For Northern blot, total RNA from rat tissue (30 ug) was _ electrophoresed and transferred to nitrocellulose, rinsed,. and UV cross-linked. . _. _ _ Digestion of rat cDNAs with EcoRI-SphI and KpnI-EcoRI gave a 457 by and 227 by specific fragment for PKC~ and PKM~respectively. The fragments were radiolabeled with 32P using a Stratagene random octamer protocol (Stratagene Cloning Systems, La Jolla, CA). Hybridization conditions were performed according to instructions for Stratagene QuickHyb Hybridization. Blots were developed overnight by film exposure at -70 °C or by PhosphorImager (Molecular Dynamics Storm S60 gel and blot imaging system, Amersham Pharmacia Biotech, Piscataway, NJ). The sizes of the ~' RNA
and PKC~ mRNAs in different brain regions and kidney were then determined by Northern blot, using probes specific to their unique 5' ends (Figure 12C). The ~' RNA
was expressed as a 2.3 kb and 4.7 kb species in brain, but not kidney (Figure 12C). PKC~
mRNA was expressed as a 2.5 kb and minor 4.S kb species in kidney and cerebellum, but not in neocortex or hippocampus (Figure 12C). These sizes were similar to those previously reported.

In all brains, whether those of neurologically normal individuals or those of patients with neurodegenerative diseases, the PKCv/~, antibody showed widespread weak, fine granular labeling of neuronal cell bodies and neuropil in cortex, subcortical gray matter, brainstem and cerebellum (Fig. 14a). The antibody consistently labeled ependyrnal cells and choroid plexus epithelial cells, but glial cells were irrununonegative (data not shown).
In AD, the PKCv/~, antibody strongly labeled a subset of NFTs in hippocampal pyramidal cells and neocortical neurons (Fig. 14b) as well as most Hirano bodies in CA1 of the hippocampus (Fig. 14c). PKCtI~,-positive NFTs generally exhibited classic flame-shaped configurations. Interestingly, while 'early' perinuclear tangles were also labeled, the more advanced 'ghost' or 'extracellular' _ tangles failed to label. Neuropil threads, amyloid plaques and granulovacuolar bodies in hippocampal neurons were generally immunonegative. ~ a The PKCv/7~ antibody uniformly labeled Pick bodies and occasional Pick cells in neurons of hippocampal dentate gyrus and neocortex of PiD (Fig.
14d).
In cases of PSP, the antibody labeled globose tangles and tufted astrocytes in the subthalamic, mesencephalic, inferior olivary and cerebellar dentate nuclei (Figs.
14e-14f). In CBD, ballooned neurons, tau-immunoreactive astrocytic inclusions in cerebral cortex, as well as neuronal and glial inclusions in the basal ganglia were immunopositive (Figs. 14g-14h).
In the a-synucleinopathies, the PKCv/7~ antibody strongly labeled all classic Lewy bodies found in the substantia nigra as well as the majority of Lewy bodies in cerebral cortex and amygdala in PD and DLB (Figs. 14i-14j). Lewy neurites in amygdala, hippocampal CA2/3 or midbrain were labeled only rarely.
The PKCv/~, antibody also labeled some glial a-synuclein-positive inclusions in MSA (Fig. 14k). Omission of the primary antibody resulted in no immunolabeling of any of these structures (Fig. 141).

Single nucleotide polymorphisms were identified in the PKC~ and PKCv/~, genes (SEQ ID NOs: 6 and 7 respectively). The sequences obtained using the genome browser (UCSC, CA) and examined for SNPs from clone overlaps and SNPs from random reads. SNPs identified in the PKC~ and PKCi/~, genes are indicated in the sequence in bold letters. For reference, exons are indicated in capital letters.

Sequence Listing SEQ ID NO: 1 TDPKMDRSGGRVRLI~C
SEQ ID NO: 2 TLPPFQPQITDDYGLC
SEQ ID NO: 3 EYINPLLLSAEESV
SEQ ID NO: 4 Homo sapiens, protein kinase C, zeta I, clone MGC:10512 mRNA, complete cds GGCACGAGGGCCCCGCGCGCCGCCGGAGTTCCGCGGAGTTGACCGGGTC
GGCGCCGTCGGTCCTGAGCGCTGCCTTCCGCGTTCCGCCGCGGCCCCACC
TGGAGCCCCCGCCCCGCGCCATGGCCGGAGCTCCCGGGGCGCAGCGCTG
ACGGCGGCGGGGGGAGCGCGCCATGCCCAGCAGGACCGGCCCCAAGAT
GGAAGGGAGCGGCGGCCGCGTCCGCCTCAAGGCGCATTACGGGGGGGA
CATCTTCATCACCAGCGTGGACGCCGCCACGACCTTCGAGGAGCTCTGTG
AGGAAGTGAGAGACATGTGTCGTCTGCACCAGCAGCACCCGCTCACCCT
CAAGTGGGTGGACAGCGAAGGTGACCCTTGCACGGTGTCCTCCCAGATG
GAGCTGGAAGAGGCTTTCCGCCTGGCCCGTCAGTGCAGGGATGAAGGCC
TCATCATTCATGTTTTCCCGAGCACCCCTGAGCAGCCTGGCCTGCCATGT
CCGGGAGAAGACAAATCTATCTACCGCCGGGGAGCCAGAAGATGGAGG
AAGCTGTACCGTGCCAACGGCCACCTCTTCCAAGCCAAGCGCTTTAACA
GGAGAGCGTACTGCGGTCAGTGCAGCGAGAGGATATGGGGCCTCGCGA
GGCAAGGCTACAGGTGCATCAACTGCAAACTGCTGGTCCATAAGCGCTG
CCACGGCCTCGTCCCGCTGACCTGCAGGAAGCATATGGATTCTGTCATGC
CTTCCCAAGAGCCTCCAGTAGACGACAAGAACGAGGACGCCGACCTTCC
TTCCGAGGAGACAGATGGAATTGCTTACATTTCCTCATCCCGGAAGCATG
ACAGCATTAAAGACGACTCGGAGGACCTTAAGCCAGTTATCGATGGGAT
GGATGGAATCAAAATCTCTCAGGGGCTTGGGCTGCAGGACTTTGACCTA
ATCAGAGTCATCGGGCGCGGGAGCTACGCCAAGGTTCTCCTGGTGCGGT
TGAAGAAGAATGACCAAATTTACGCCATGAAAGTGGTGAAGAAAGAGC
TGGTGCATGATGACGAGGATATTGACTGGGTACAGACAGAGAAGCACGT
GTTTGAGCAGGCATCCAGCAACCCCTTCCTGGTCGGATTACACTCCTGCT
TCCAGACGACAAGTCGGTTGTTCCTGGTCATTGAGTACGTCAACGGCGG

GGACCTGATGTTCCACATGCAGAGGCAGAGGAAGCTCCCTGAGGAGCAC
GCCAGGTTCTACGCGGCCGAGATCTGCATCGCCCTCAACTTCCTGCACGA
GAGGGGGATCATCTACAGGGACCTGAAGCTGGACAACGTCCTCCTGGAT
GCGGACGGGCACATCAAGCTCACAGACTACGGCATGTGCAAGGAAGGC
CTGGGCCCTGC-TGACACAACGAGCACTTTCTGCGGAACCCCGAATTACA
TCGCCCCCGAAATCCTGCGGGGAGAGGAGTACGGGTTCAGCGTGGACTG
GTGGGCGCTGGGAGTCCTCATGTTTGAGATGATGGCCGGGCGCTCCCCG
TTCGACATCATCACCGACAACCCGGACATGAACACAGAGGACTACCTTT
TCCAAGTGATCCTGGAGAAGCCCATCCGGATCCCCCGGTTCCTGTCCGTC
AAAGCCTCCCATGTTTTAAAAGGATTTTTAAATAAGGACCCCAAAGAGA
GGCTCGGCTGCCGGCCACAGACTGGATTTTCTGACATCAAGTCCCACGC
GTTCTTCCGCAGCATAGACTGGGACTTGCTGGAGAAGAAGCAGGCGCTC
CCTCCATTCCAGCCACAGATCACAGACGACTACGGTCTGGACAACTTTG
ACACACAGTTCACCAGCGAGCCCGTGCAGCTGACCCCAGACGATGAGGA
TGCCATAAAGAGGATCGACCAGTCAGAGTTCGAAGGCTTTGAGTATATC
AACCCATTATTGCTGTCCACCGAGGAGTCGGTGTGAGGCCGCGTGCGTCT
CTGTCGTGGACACGCGTGATTGACCCTTTAACTGTATCCTTAACCACCGC
ATATGCATGCCAGGCTGGGCACGGCTCCGAGGGCGGCCAGGGACAGAC
GCTTGCGCCGAGACCGCAGAGGGAAGCGTCAGCGGGCGCTGCTGGGAG
CAGAACAGTCCCTCACACCTGGGCCCGGGCAGGCCAGCTTCGTGCTGGA
GGAACTTGCTGCTGTTCCTGCGTCGCGGCGGATCCGCGGGGACCCTGCC
GAGGGGGCTGTCATGCGGTTTCCAAGGTGCACATTTTCCACGGAAACAG
AACTCGATGCACTGACCTGCTCCGCCAGGAAAGTGAGCGTGTAGCGTCC
TGAGGAATAAAATGTTCCGATGAAAAAAAAAAAAAAAAAAAAAA
SEQ ID NO: 5 mRNA sequences: PKCzeta II (PKMzeta) mRNA and protein Sequence Range: 1 to 2252 CGAUGUCGCA UUUUCAAGGU CCGCUGAGUC CGAGCCCUGC CUGGGUCUGG

CUGCUGCCCG CCCGCUCUCU GGACUGUGCU GAUGCAGAGA UGCUUGUUUU

CCUGUGACGU CAGCGUCAGC UCCUGCACAU CCAUGCCGUG UUUUAGUUUG

UGCCUCAGCU GCUGGCUACA GCUUCCCGGG GGAGCCGGGU ACCACCCGGG

CCUGGAGACA UGAGGAGGCA GGGAUGUGAG GGGCGGGGGA CAGGACAGCC

GGCCUUCCGU UAAAUAUCUG CUCCUCGCGC UCGAGCCUCC CUGCCUAUUG

UCGGGGCCGG AGGCGAGCCG ACGCAGCAUC AGCUCGUCAA CGGGAAGGAA

GAUGCCUCCC UGCACGCCCG CCGCGCACAG AGCAUAAAGA AUCUGCGCUG

AGGAGGCAGG AGAAGAAAGC CGAAUCUAUC UACCGCCGGG GAGCCAGAAG

AUCGAGGAAG CUGUACCGUG CCAACGGCCA CCUCUUCCAA GCCAAGCGCU

UUAACAGGAG AGCGUACUGC GGUCAGUGCA GCGAGAGGAU AUGGGGCCUC

_.__ _ GCGAGGCAAG GCUACAGGUG CAUCAACUGC AAACUGCUGG UCCAUAAGCG.- --._.

CUGCCACGGC CUCGUCCCGC UGACCUGCAG GAAGCAUAUG GAUUCUGUCA
M D S V>
a >

UGCCUUCCCA AGAGCCUCCA GUAGACGACA AGAACGAGGA CGCCGACCUU
M P S Q E P P V D D K N E D A D L>
a TRANSLATION OF HSPKMZMRNA [A] a >

CCUUCCGAGG AGACAGAUGG AAUUGCUUAC AUUUCCUCAU CCCGGAAGCA
P S E E T D G I A Y I S S S R K H>
a TRANSLATION OF HSPKMZMRNA [A] a >

UGF.:CAGCAUU AAAGACGACU CGGAGGACCU UAAGCCAGUU AUCGAUGGGA
D S I K D D S E D L K P V I D G>
a TRANSLATION OF HSPKMZMRNA [A] a >

UGGAUGGAAU CAAAAUCUCU CAGGGGCUUG GGCUGCAGGA CUUUGACCUA
M D G I K I S Q G L G L Q D F D L>
a TRANSLATION OF HSPKMZMRNA [A] a >

AUCAGAGUCA UCGGGCGCGG GAGCUACGCC AAGGUUCUCC UGGUGCGGUU
I R V I G R G S Y A K V L L V R L>
a TRANSLATION OF HSPKMZMRNA [A] a >

GAAGAAGAAU GACCAAAUUU ACGCCAUGAA AGUGGUGAAG AAAGAGCUGG
K K N D Q I Y A M K V V K K E L>
a TRANSLATION OF HSPKMZMRNA [A] a >

UGCAUGAUGA CGAGGAUAUU GACUGGGUAC AGACAGAGAA GCACGUGUUU
V H D D E D I D W V Q T E K H V F>
a TRANSLATION OF HSPKMZMRNA [A] a >

GAGCAGGCAU CCAGCAACCC CUUCCUGGUC GGAUUACACU CCUGCUUCCA
E Q A S S N P F L V G L H S C F Q>
a TRANSLATION OF HSPKMZMRNA [A] a >

GACGACAAGU CGGUUGUUCC UGGUCAUUGA GUACGUCAAC GGCGGGGACC
T T S R L F L V I E Y V N G G D>
a TRANSLATION OF HSPKMZMRNA [A] a >

UGAUGUUCCA CAUGCAGAGG CAGAGGAAGC UCCCUGAGGA GCACGCCAGG
L M F H M Q R Q R K L P E E H A R>
a TRANSLATION OF HSPKMZMRNA [A] a >

UUCUACGCGG CCGAGAUCUG CAUCGCCCUC AACUUCCUGC ACGAGAGGGG
F Y A A E I C I A L N F L H E R G>
a TRANSLATION OF HSPKMZMRNA [A] a >

GAUCAUCUAC AGGGACCUGA AGCUGGACAA CGUCCUCCUG GAUGCGGACG
I I Y R D L K L D N V L L D A D>
a TRANSLATION OF HSPKMZMRNA [A] a >

GGCACAUCAA GCUCACAGAC UACGGCAUGU GCAAGGAAGG CCUGGGCCCU
G H I K L T D Y G M C K E G L G P>
a TRANSLATION OF HSPKMZMRNA [A] a >

GGUGACACAA CGAGCACUUU CUGCGGAACC CCGAAUUACA UCGCCCCCGA
G D T T S T F C G T P N Y I A P E>
a TRANSLATION OF HSPKMZMRNA [A] a >

AAUCCUGCGG GGAGAGGAGU ACGGGUUCAG CGUGGACUGG UGGGCGCUGG
I L R G E E Y G F S V D W W A L>
a TRANSLATION OF HSPKMZMRNA [A] a >

GAGUCCUCAU GUUUGAGAUG AUGGCCGGGC GCUCCCCGUU CGACAUCAUC
G V L M F E M M A G R S P F D I I>
a TRANSLATION OF HSPKMZMRNA [A] a >

ACCGACAACC CGGACAUGAA CACAGAGGAC UACCUUUUCC AAGUGAUCCU
T D N P D M N T E D Y L F Q V I L>
a TRANSLATION OF HSPKMZMRNA [A] a >

GGAGAAGCCC AUCCGGAUCC CCCGGUUCCU GUCCGUCAAA GCCUCCCAUG
E K P I R I P R F L S V K A S H>
a TRANSLATION OF HSPKMZMRNA [A] a >
5g UUUUAAAAGG AUUUUUAAAU AAGGACCCCA AAGAGAGGCU CGGCUGCCGG
V L K G F L N K D P K E R L G C R>
a TRANSLATION OF HSPKMZMRNA [A] a >

CCACAGACUG GAUUUUCUGA CAUCAAGUCC CACGCGUUCU UCCGCAGCAU
p Q T G F S D I K S H A F F R S I>
a TRANSLATION OF HSPKMZMRNA [A] a >

AGACUGGGAC UUGCUGGAGA AGAAGCAGGC GCUCCCUCCA UUCCAGCCAC
D W D L L E K K Q A L P P F Q p>
a TRANSLATION OF HSPKMZMRNA [A] a >

AGAUCACAGA CGACUACGGU CUGGACAACU UUGACACACA GUUCACCAGC
Q I T D D Y G L D N F D T Q F T S>
a TRANSLATION OF HSPKMZMRNA [A] a >

GAGCCCGUGC AGCUGACCCC AGACGAUGAG GAUGCCAUAA AGAGGAUCGA
E P V Q L T P D D E D A I K R I D>
a TRANSLATION OF HSPKMZMRNA [A] a >

CCAGUCAGAG UUCGAAGGCU UUGAGUAUAU CAACCCAUUA UUGCUGUCCA
Q S E F E G F E Y I N P L L L S>
a TRANSLATION OF HSPKMZMRNA [A] a >

CCGAGGAGUC GGUGUGAGGC CGCGUGCGUC UCUGUCGUGG ACACGCGUGA
T E E S V>
TRANSLAT >

UUGACCCUUU AACUGUAUCC UUAACCACCG CAUAUGCAUG CCAGGCUGGG

CACGGCUCCG AGGGCGGCCA GGGACAGACG CUUGCGCCGA GACCGCAGAG

GGAAGCGUCA GCGGGCGCUG CUGGGAGCAG AACAGUCCCU CACACCUGGC

CCGGCAGGCA GCUUCGUGCU GGAGGAACUU GCUGCUGUGC CUGCGUCGCG

GCGGAUCCGC GGGGACCCUG CCGAGGGGGC UGUCAUGCGG UUUCCAAGGU

GCACAUUUUC CACGGAAACA GAACUCGAUG CACUGACCUG CUCCGCCAGG

AAAGUGAGCG UGUAGCGUCC UGAGGAAUAA AAUGUUCCGA UGAAAP~~AAA

SEQ ID NO: 6 Genomic sequence for protein kinase C iota/lambda (human), (exons for PKC iota/lambda~in capital letters and single nucleotide polymorphisms are indicated in bold) >chr3:171261193-171342120 GCGCGGTTCCGGCTGCTCCGGCGAGGCGACCCTTGGGTCGGCGCTGCGGGCGAGGTGGGC
AGGTAGGTGGGCGGACGGCCGCGGTTCTCCGGCAAGCGCAGGCGGCGGAGTCCCCCACGG
CGCCCGAAGCGCCCCCCCGCACCCCCGGCCTCCAGCGTTGAGGCGGGGGAGTGAGGAGAT
GCCGACCCAGAGGGACAGCAGCACCATGTCCCACACGGTCGCAGGCGGCGGCAGCGGGGA
CCATTCCCACCAGGTCCGGGTGAAAGCCTACTACCGCGGgtgagtgtcctgggacagggc ggtgggcgggaggggacaggccggctccactcggcctggaggaggggagggtgaggggct ggaggtgttgtgggcggattgggctgggcgggcgggcggctccggtgactcagggtgagt gacgaagtgataggggtgggggcgaagcaaggggatgcagtactgggggcgcccccaggt atggcggtgcggggagccgaggggccagagtagggtccgagaaggaagctagggttagag taggtgcacctggtgtggacgagagactcgcctcctgagagctttgtaggggccttgcat ccttaagtctgggtgtatttggggttgcgagttgaggattecaagtgatgccttagttaa ctcagtttgctgtggggatagaaaacgggacttcttcagttagctgtccgttttgattac cagcaggcctaacgcctctggttctetgagatatacctccatccccgttgtgttcacgta gtgtatctgcactgccagtatattagacataggggttgtatttaagaatcaagtcgatgc gttttcagggacgtgcagtgggtacttacgtgtcgtcaagattaagttgcatgtgtgtaa atcaaaattttgtgagcctttctttctcagtgttgtttcaacgactacccgatagggtga gatactgcaaggtgaggagactagcctagttacagttttaaattctctgatcttcactcc cttactatggttacaagaaaaaacccagttctaagttcattgtgttaaatcattttctat _ _ _ cagtgacgcaaagtgccccccttcctttaaattcagttgtggtttgaatttttttttgag ataattatgtttaggagcattagaaacgtgaaatgttagtgtgaccataaaggttggaga ctgagaagtcacagaaaacccagctactttggcttgccttactgcttgtccaggtagaag taaattgctttaaaaaactcaagcagtgctaggttgaaattttaatgcatacttttacat tcctgagdggatcagtgaagatagcaaactctcaaactacctctcttgttttgatttcaa agaaaatctgagcccctaaatgttgtattgatttgatgtaaggacttttttttttattat tatactttaagttttagggtacatgtgcacaatgtgcaggttagttacatgtgtatacat gtgccatactggtgtgctgcacccattaactcgtcatttacattaggtatatctcctaat ggtatcectcccccctccccccaccccacaacagtccccagggtgtgatgttccccttcc tgtgtccatgtgttctcattgttcaattcccatctgtgagtgagaacatgcggtgtttgg ttttttgtccttgatgtaaggacttttaaatttgctgccatgaagcetctggcctctgtt tattattagcttgactgtatgcaggagtagtttattggagttatattggacagtatgata actttgtgtttaagcaggtaaaactgattaaggaggtttttattttaaatcagtaccaag aaacgtgtggatattttttaaagtttgtagttgtcacaagagctgttttgacttgaggat ggtcagccatgaactttgcaaggtgagaaaaaagcttcctttgcttttttttttttaaac ccttacctgtaatttgatgaatgagatgtttcactttattcttttattttatttttgttt gtttgtttttgagacagggtcttactctgttacccatgctggagtgcagtggcacaatct cggctcactgcattctccgcctcccgggttcaagcaattcgcctgcctcagccttctgag tagctgggattacaggcatgtgccaccacacccggctaatttttgtatttttagtagaga cggggtttcaccatattggccaggcatgtcttgaactcctggcctcaaatgatgcgctcg tcttggcttcccaaattgctgggattacaggcatgagccactgcgcctggccctaaggct ttcaataaattcttattaattgagatcatcttctccaatgagtctatgaaaggtaagaaa ttagtgcttctattttcccatttgtattagtttgacacatgtaaataggcccagttagta aatgaaaatcattgtaaactcctttgagaagaaatcaaagtcttgctgtacttcatgaat ttagatagcaaattatcttggcttattgctccagttattaaaaagaagagaataaggaca tacagettctttagtgtttgactgcaatttttccaagacattcaaggtaacattgtettt taaaatctgtgaaattttgctgcggcgcaaataacctcttgcccattgtatactggtctt tgctcaatgaaagctttctaatggtaccttcatttcaagcctcatttaaagacaatatca gcactctaaattgtaccaaattcctgtcctctgaaattagatgttaagattatgtgtttg tatagtctaaactgatgattgtggtattacatagtcagctgctcattaatatagatgaag ctaaaatgagtcacggacaaggatagttaataaacaggttggctaactagaacacctacc tgattttaaaatagaaaatccttcctttataccaagaaatgtgagaacattctgcatttg aaaaagttttettttctctccaatettctgaagggccattattacatagcatttcctcta tccetctacacttttcttttcttttttttttttttaaatagagacaaggtctcaccgtgt tgcccaggctaateccaaactcctgggetcaagtgatectcctgcctcagcctctcaaag tgctgggattacaggtgtgagccactgtacctggctccactacccttttctaacaatatt tctttccagtgaatgttgactcatttaatagccagcattttttttagtgaaaaaattgcc ctctcttttcaaagatgtgtatagtgttattattctgttaagcttgatctcagtgaaaac gtgtaatctctctagatctaataacatttaatttttttctaatttttattttattttatt ttatttatttatttttttggagatggagtctcgctctgtcacctgggctggagtgcagtg gcgtgatctcggctcattgcaacctccgcetcccaggttcaagggattctcctgcggctg cctcccgagtaggtgggactacaggcgcecaccaccacgcccagctaatttttgtatttt agtagagacgggttttcaccatgttggccaggttggtctcccaacttctgacctcaagtg atccacccacctcggtctcccaaagtgttgggattacaggaatgagccatcttgcccagc caatttacatctagtttttaagcaagagattaatagcactgaaaattcaattttattgga caccacatcttacttagatgcctttctcatggcctgcaccegtcttttcctagcaaggaa gcttttcagtgaggggccttcagttattacetagtgctagtagtttggaggaagagaaac aggtttcattaattagtgataaactgtcaatgtatgtgcttatccttatataaaattact tgctattatgggatagactttaacaaggcaacatctggactgctcatttetttacattat atatgtatggaaatttttgcagaaagcttgtgaaagttctttttaaaccgctgctgtcaa gtagtaataacaatacagaggattccttctgtgcacatctagaaataaaagattaactct ttgcatatttggaatagctgcttcagtgaagaagtatgtaggatttttcttactgtgaac aagtcttggcaagacttgtttttgaaagaaatgcaagattattttagcaatatactttag taatggttctgaggaaatacaagtggtatcttgagggttggggggatgttagctaattgg tcttagagcttcagccatggcacctaatectagggcagctgatccatagcttggccaaag agagaaaaaaatagagcatgctagcctggtgccaaaaaacccaaaccaaacacaaaaaac cctcagaaatttgaatgagaaaatatggagataaaattggtcagcactgggaactgaagc tggagttggagggagagtctggcgaggccagaactgacaatgtgcaaatgaaagatgtga agaagcagaaactgaggaagcaaaggagaaaggagcaactctgcacagaaaaattctccc cacaggtccttagttcatgatggctttctaatgcaactgcagccctccttttacaacttt_. ___ agtgtctgttttttttatgattgaaatgagcctaatttaaacatagattttaaaaattcc agtcttgcttaagatttcaaatataaccagagatcattcaaactgagtttagtaaatatt gttgaacgtccgtaatccaggcacatgatgctgtcgtaggcacagagaatgtagaggtag gtaaggctctgcctttaaggaattaagagacttgtggagggaaggacatataagagttac aatagaaacaatttaatttgaagtacctatgtaaggtatttgcaggaatagacgttgggg aggagtttggggtgatggaagccttcctagaggaaatgtctgaggcttttaaaggataac taggagtttgcctggtgaataatgatgttaggtgggtgttataggcattaaacaaccaca tggtaagtttgcagaattaagatcactttggctgttagtctcatattcattccttattag gatataaagtatgaagtgggcactgatgagaaatgaggctaagaaagttcacaggggcta gattgtaaagacccttgaatgtcatactgcagagtttagactttttctcattgatgaaaa ttctaagtaagagaaatacatgatcagatttgcattttagaaagataacacttgaaatta gtatgggagatggattggtgatggatgaaactaatttggaggcttttgaagtagtccaga tgagatattttaaggagagagaaaagagtgtatggattcggtggaaattttaaggggtag tatcagtagaattaaagatagtcttgtaggggtgacgggagttggacaactcataggttt ctcgtttaagagagactggggaatgtggaagagatttgtgggagaagttaattaattggc tggaacaattcactgaattttgagttctaggtgtttatgaggcattcaggaggaaatgtc agaaagaatggagcaattatttattgtctgtctactctgtgttgcaagcactgtgcttga cagctaacctatgtaggaatgtggctgagaacgataatagaaacaaaaatgacaccagtg gccaaatacagatcacaaaggcaaggcactaaaactaaattttaaaaatatagaaataca gaaagaggctgggtatggtggttcatgcctgtaatcccagcactttgggaggtcagggca ggtgaatcacttgagcccaggaattggagaccagcctgggctgaatgtggtgaaacccta tctctacaaaaaaattagcctgtagtcctagctactaggagggcgaggtgggagaatcac ctgaggccaggaagtcaaggctgcagtgagctgtgattgcaccactgcactccagcctgg gcaacagagtgagaccctgtctcacacacacacagacatacacacacacaaatatatata tatatacacacacacacacacacacacacatatacatacacacacatataaagttcccct gtagtctetcactcccaccttattttattttattagtttatttttatatatttaaagggt acaagtgcagatttctttctttcttacatgtttgtatcatgtagccatgaagtctggtca cttagtgtacccatcaccggaacagtaaacagtaaaacccagaaaattacctgtacccga taggtatttttcaaccctcacccccctcccaccttttgtagtctccaatgtctactattc cctctttatgtecatgtgtaccctttgtttagctctcacttataagtgagaatatgtggt atctggctttttgtttctgatttttttgactagggataatggccttcagttccatccatg ctggtgtagaagacgtgatttcattattttttatggctgtctcactcccactttctagag atagccattgttaacagttagggatattctatatcatatcggtatatttataagtataga tatgtatgtgcatacacacacacagacatacccttttatttttccaataaatgagttcat atttccacacatgcatctgcaacttgattttaaaaatcgtggtcatcttttcattccagg gtagacagacctctttatagttggtaatacagtgttctacagttgttgttgttgttttaa gagacagagtctgattctgttgcctacgctggagtgcagtggcatgatctaggccctctg cagcctcaaccactctgggttcaagcagtcctcccacetcagcctcctgagtagctagga ttagctcacgccactaggctcagctaattttttttaatatgttttgtagggacggggctg gtctcaagctcctgtgctcaagtgattctcctgcctcggcctctcaaagtgtagaaatta caggcatgagccattgcgcccagccaccataatatgtttaatcttttttcggattgatga acatttaaagttgtcttcatcaactcactatttcaaataatgttgaaggaacetccttat atttaatacatattcttgtaaatatggtcaaagatatgcctatcttgaaatatgatattg tttcccaaaagagcttaatttacattcttaacaacaggactagtgaagcttctgccttat attcccattgcatgttatctgtcttttaaatttttgactgtcagattggcaaaaaatggt aatttatttttacaagtatcttttatatattaatgatcatttgtatttcttctggattgt tcctattttacccattttctattgtattatttttcttattaatttgttgacaggacattg acattttgttaaagttgccagcatttccccaatctgttgctagtctggagtttttcgttt ttatgtcatcaaacctgtcctttttaaaaatttccttgatagtttctggatttactgtct taggtaaaagtgtttttcatctaaaaatattctatttttcttctattatgcaactttttt ttttttttttttgagacagagtcttgctttgttgcccagggtagaacccagtggcgtgat ctcgtcttactgcaacctttgcctcctgggttctaacaatcctcctgcctcagcctccta agtagctgggattataggcgcacgccacaacacccggctaatttttgtttgttttttgag acaaggtcttgctcagtcgcccaggctggagtgcagtggcacgatcctggctcactgcag cctetgcctcctgggttgaagtgattctcctgcctcagcctcccaagtagctgggattac aggcatgcgccaccatgtccggctaattttttatttttagtagagacagggttttgccat gttggccaggctggtcccaaactcgtgacctcaagtgattcacccgctgtggcctcccga agtgctgggattttaggcgtgagccactgcgectggcttattatgaaacttttaaagtga ttatcttttcagtgaatctggtattttggggtttagtcatttatagggtactgacacaac ttttt.ttttctccaaaatttattctaataccattattgggcagattgtcc ttcaccact.
gatttgaaatggtaactctgttatgtactaaatttcccacaatgtgcgtaggtactttct attgtttcattgattttaggggagagatctatttttgcacataccactattggtttaatt attgtaatattatagttaactttgatatatgttatggaatggcttgattcattatttaat tttttttttttgttttttttttttttgagatggagccttgcactgtcacccaggctggag cgcagtggcgtgatcttggctcactgcaacctccgcctcccaggttcaagcgattctcca gtctcagtctctcaagtagctgggattacaggcaaggcgctaccatgcctggctaatttt tgtatttttagtgaaaatggggtttcaccatgttggccaggctggtctggaactcettac etcaggtgatccatctgcctcggcctcccggagtgttgagattacaggcttgagccaccg tgcccggcctattcctatatattttataatcatgtgcttttgtgaatggggtcttcttgt agacctattacatactgttttctttttgtatgtttaaattaaactttccaccttactaat aatttaactgtcttagaatttttaagctagataatgtcatctgcaagtagcaattttgec tcttcttttctatatcttatttatttatttattatttattttatgttttttgagacagag tctcactctgtcgcccaggctggagtgtagtggcgtgatctcggctcactgcaacctccg cgtcccaagttcaagtgattctcctgcctcagcctcctgagtagctaggattacaggcgt gcaccaccacacctggctaatttttgtagttttagtagagatggggattcgccatgttgg ccagactggtctcgaacgcctgacctcaggtaatccacccaccttggcctcccaaagtgc taggattacaggtgtgagccactgcgcccagccttatttatttttagccataggctagaa ttttctagacagtattgaattatagtaataatctcttatcttagtgaaatataatagaaa aatttctgtcaattaaagaaaaaagcttttaaagaattaaagttagtgttattcagaaat gttactgaggccgagtgtggtggctcacgcctgtaattgtgccactgcacttcaacctgg gtgacagagcgagactctgtctcaaaaaaaactcaactgaaaaaagtggaacaaaagaaa aagaaccatgataagtattttgcactttttttttttttgaggcacatttctactctgtca cccaggctgagtacagtggtgtaatcacagctcactgcagccttaactgcccaggctcac gcagtcctcctacctcagcctcccaagtagttgggactgtaggcacacaccactatgtct ggctaatttttaatttttttgtagagacaaggtctccctgtgttgcccaggcaggcctcg aactcctgtaccgaagcgatcctcccacattggcctttcaaagtgctgggattatggcat gagccaccttgcctggctgcactcatttattttcatttatttttcattttttgagtcagt gtcttcctccatcacccaggctagagtgcaatgacatagtcacagctcactgcagcctca acttcctgggctcaagctgcacttatttagtcttcatgataatactcagaggcagatatg attatctccatttttcagataacattgagacttactaacccacaatacaaagctgggtgt gtttttttttttagagacagagtcttgctctgtcgcccaagctgaagtccaatggctcga tcatggctcactgcagccttgaactcctgggctcaaatgattctcgtgagtagctgggac tacgctatgettggctaattacaaaaaaattttttttagagacagggtcttgttctgtca ctgaggctggccttgaactcctgaggtgatcctcccgcetcagcatcctgagtaggtggg attacaggcacgagccaccttgcccagccaaaactggaccttgaacttcaaagagatttc tcttttcccettactacattgacagggetttataacattgettttttactttattgttac attcatatttcacaattgttatttttgaattcactatcttcttcattattaaaaggtgga aattgctttatgaccttttttataattaataatttggggggtgatactttgagattatat gaatactetagtcccccaaaacattttgcccaatggtcttaccattcatggataatcctg cctaaaccaattattataatggttattgcaaataaaagtattttttcgaatagcctaatt tagaagaaaagcttacactgaggtagcagaaggactgaatgtgattettttgggggttta tttttaaaagcaattagtcctaaggaaaaactttataatagattctatattttagaatat aggcacattgaaagcagtttgtettctgaagctcaatagcaaaataaaaaatgcttaaaa aaattcagctaaaaccatatctaaatttgccattttgggaatctttgtgataaagcagat tatattctgttgaggatcagtggtaaaataatttatgctagtgctgaagttaaactggaa aaaacatcatacgtgcataatttgttttatacetttagaatgtaatatctttattttgca gttcatttttagctttggtactgtaacaaggatctggtgattgtggaatgttatgaacat agtggtttcgcaattactgagagctaagtgtttatataaaactcccttgaatgttttagt tcctggaacttaaggagtggtagttgataaagcataactccttcattgagtctctgatgg gtatctatacttaaacttttttttttttaaacagaatctcactttatcatecaggctgga gtgcagtgacgcaatcacggctcactgcagcctccgcctcctgggttcaagcggttatcc tgcctcagccteccaggtagctgggattataggcacccaccaccatgcctggctaatttt tgtatttttagtagagacggagtttcactgtgtttgcegggctgatttcgaactcctgac ctctagtgatccgcccacctcagcctcccaaagtactgggattacaggtgtgagccacca cacccagcctatacttacactttttttttttttttttttgagatggagtttcgetcttgt tgcccaggctggagtgcaatggtgtgattggttcactgcaatctccgcctcccgggttca agcgattcttctgccccagcctcctgagtagctgggattacaggcatgtgccaccacacc cagcaaattttttatttttagtagagtcagggtttctccatattggtcaggctggtctcg aactcccaacctcaggtgatccatctgcctcaggctcccaaagtgctggggttacaggtg _, __ _ tgagccaccacgcccagccttatacttatactttttaagtattacacagatgtcttaaaa _. _~,_ gtatttgtatgttctgataagtgttttttagcttttgaaaagtaaaatttatgaaaaagc cttgttgtttacaaatatgtttacctttctgttaattttaaatgtggactttgataagga agttatatttcgatgatatccagtgtaactaattttttccctcttattcaagaaagataa ttttacacttattctttgacagagaaatttcatagaattttcttcttctaatttaattcc agaatacattctctcaaccctatgccctcatactagtaaccttgagggttctttgaaaga aaaattgctttaaatcaagcaattetcttttgtcattaaaataagctattttctattttt atttttaaaaactatttaaaacaatataattatgcaagtgtgtatatatgtatttgattt ttttgttttcttttgtttttatttatttttttgacacagtctcctctgttgcccaggctg gagtgcagtgatgtgatctcagctcactgtaacctacacctcccatgttccccccctgag aaggatcctcccacctcagcctctggctaattttttttttgtatttttagtagagacggg gtttcaccatgttgcccaggctggtcttgagctcctgggctaaagtgatctgcccagctc agcctcccaaagtgcatgagccaccgtgcccagcttgatattttaatttttacttgaatg aaatcatttactgaaagcaatacatgttgatgcacacacaaaattactgaagttcatcaa attgtcaagcattcagtaatatatacagcattattatttttaatcattttcaaactgaaa actccttttctttttcagGGATATCATGATAACACATTTTGAACCTTCCATCTCCTTTGA
GGGCCTTTGCAATGAGGTTCGAGACATGTGTTCTTTTGACAACGAACAGCTCTTCACCAT
GAAATGGATAGATGAGGAAGgtgagtggtaaagacagggctgcctgtgtaagcattttaa gatcttattctatcatttgttgtaaaaatataatgagtcctaaaaagtttaagaggaaag actattagaaatttgatgccattcttgttttttctttaagtatttaaaagaatactgaag agcacaatettttttttgccccttttacgccaaaatgatgtgaaattaacttgacttttt ttttttttttttgagacggagtctcgctctatcgcccaggctagagtgcagtggcctaat cttggctcaccaaaacctccacctcccgggttcaagcgattctcctgcctcagcctceca agtagctgggactacaagtgtgcaccaccatgcccggctaatttttgtatttttagtaga gacgggggtttcgctatgttggccaagctggtctcaaactcctgaccttatgatctgccc acctcggcctcccaaagtgctggcattgcaggcgtgagccactgtgcccagcctaacttg acttttttaagcataaggtaagcatctcatcaaatagtgtgatgttttactttaattttg ttttttctttgaattaaattttttttttttattttttaaagacagggtcttgctaagttg tccaggctggtctcraactcctggcctcaagtgatcttcceatcatgacctcccaaagta ctgggattgcaagcaggagccactgcattcagcttcactttattttttaatttaaatttt ttttttttgagacagagtctggctctgtcgcccaggctggagtgtagtggcatgatatca gctcactgtaacctccgcctccaaggttcaagcaattcttgtgcctcagcctcccaagta gctgggatacaggggtgcaccaccacacccagataatttttgtatttgtagtagagacgg ggttttgacgtgttgcccaggctggtcttgaactcctggcctcaagtgatctgcccacct aggcetcccaaagtgctgggattacaggtatgggecaccacacetggcccccagcttcac tttaattttgaatatgtgttgtcttatattttaatttaagagattacctatttttaagct gaatattaccttaaagaaaatattgtggaatgaaagtgattttgacaatcattatttcaa agtagtggcagaaacctgatacctcagtgacttgtactcagaaaacatttatcatatatg taggcttacgcctgtaatcecagcactttagagtctgaggtgggaggattgcttgaggcc aggagtttgagaacagcctgggcaacattgtgagaccctgtctctacaaaaagtttttaa aacttatctggtggtagcgtgcacctgtggtcccagctacttgggaggctgaggtgggaa gattgctcgagcctggaaggtcaaggctgaagatgggccctgattgtgccactgcactcc agcaacaaagcaagcaaagcaagaccctgtctcaaaaaaaaaaaaaaaagaaagaaaaag ggaaaaagaagcaaatatctgtgtgctgaggacagacatttcctatcctcaaacccatag tctgatagggagatggacacatgtgtaacaaatgtgataaattctggaacataaacgcat aggggccttgaggaatacaaaggaagacacatctataatacatctgcaatgtttgacata aacctgtaacagagtagaagtttttgaggtagaggaggtgaggagaaaaccatataggct gaagaagaatatgtagaaaggcacagaaatgtgaagaacatgatgagtgaaaagcagtaa ttcactgtatctgaagtatgaagtggtgaagtatgaattggcctacagtttaacaggctc cacgggtgagttgtatgaatacagaaatttgtttgagaagcatgagactagatccccaag agctttgcagatcacattaaattttattttacatgactattatggaagtctagttaaaag gtaccctaaagaaagggtgggttgggggtgagggataaaggcctacatattgggtacagt gtacactgctcaggtgataggtgcagcaaaatetcagaagtcaccactaaaagaacttac tcatgtaaccaaacaccacctgctccttgaaaacctgtggaaataaaaaaagagagaaga taccctaaatatactactttttttacaatagttttctgttaattgttatacaaatagaat ttcattttaaggaatgtcataatatttagctcaatatttgggatcatttctatcttccct gatataaagaactctggaaagtcattattgaagctccaagctataggtaaacataaacac attctcattttttaaaacagtgttcctgaagtaattcatgttcactgttcaggaaaaaaa gtagtgcaaaaatttatgaaatgtaaaaagaagcctcctgtttttccttttttctctctc ctccctcaccaattccaattgtaagagaatagcttagtatgtatccttctatatattttc .._.,~t~tgcatttgcaaacgtgtatgtatgtt_tetataaattctttattaacagttttattaac _ _ atgacaaatgacatacagctgatattttgcagacctggtgggcatggggagcttggagcc cagtgccacccaccctggccctccatggccttaaaaaaaaattatatggggccgggcatg gtttctcatgcctataatcccagcattttgggaggccgaggcgggtggatggcctgaggt caggagttcgagaccagcctgaccagcatagtgaaaccccatctctactgaaaatagaaa aattacctgagcgtggtggcgggtgcctgtaatcccagctactagagagggtgaggcagg agaatcacttgaacctgggagacggaggttacagtgagctgagattgtgtcgttgtactc ctgcctgggcaacagagcgagactccatttcaaaaaaaaaaaaattatatacaaatcgtt atgcagtgttttcctttatagtatgcgctggacattttttcatttcagtgtacttcaatt tgcatcattactctttttttttttttagtactgcatagtattacatattatagatgtttc atgattaatcccttatcgatggacatttggactatttctagtttttcactaccataaaca atatataatgaacatttcttttctttttttttttttttttgagacagtctcactctgttg cccaggctggagtgcagtgtctcgatctccgcccactgcaacctcctcctccttggttca agcaattcttgtgecccagcctcctgagtagctgggattacaagcgtgcaacaccatgcc tgcctaatttttgt~.tttttagtagagacggggtttcaccatgttggccaggctggtctt gaactctggcctcaagtgatccacecgccttggcctcccaaagtgctgggattacaggca tgagccaccactcccagccttatttatttatttctcttttaatacagaggctgggttctc actatgttgcccaggctagtcttgaactctggccttaagtgatcctcctgacctagcctc ccaaagtgctgggattacaggtgtgagccactatgtcaaaacatatgtatatcaaaacat catgttatataccataaatataatttttgtccattaaaaaattaaactagtttttcacac aactacatgaaatgagaggattttttcattcttgcccttaccaaccttagatatgaatca taaacatttttaaagatcagtaagtgaaatgctaacctggtatttcaaattttgcattaa gaggaaagttgagtatctttatctttttgacetaccctatcacaaagatagtttaaatat ggttacttataaatgtcatgactatctcacaatatgtcttcagccagaaaatgagactat atataatttagcacagtgtgcaacttatgcttagcattcaataaaatgcttcttatcata aatgaatattcttattttaatcctgatcatttcataccatttatttgctgattagagttg tttttcagtcaatgattttcaaattgcagcacacataggcatcactggataatgcttttt attagacgtacttagtttagcgatagtccattaaacgtttttataatacctttgtattat ecttgcctggagagttctgttcccagattgtcacctggctgtctctcatcattcaggttt taactcaaatgtcatgtcctccaagaagccttcctatctccattcattttgtatcttctt gccctgttttttctcttgtatggtagagtgtttttttttttttgtatggtagagtgtaag ctecatgagagcagaggtcttgtctgttttgttcatgttggagctgcagtgcctagagca atactaaataatactatgctcaaaaaatatttgtggctgagtgcggtggctcatgcttgt aatcccagcattttgggaggccaaggcagaaggatcccttgagcccagaagtttgagacc agtctgggcaacatagtgagatagtgagaccctgtccctacaaaaaaaatttttttttta gttagctgggcatggtggtacacacctatagtctcagctactcaaaaagctaaggtggaa ggattgcttgagcatgggagatggaggctgcagtgagccatgattgtgccactgcactcc aacctagg~aacaaagcaataccctgtttccaaaaaaaagatatatgtgtatatatatat ttgtgagttgtacaagaggctagcaacaagcetttccctggtttaattttgcttcagtta ttggagacttaagcattgacagttactgtttattctgttttttttttcttaaagtagcat attttaattaacagatgcacatagtaaattaactttctgatgcaacagtcttattataat gcatttcatacttctttctccctaagtagctattaagtttccaagttttctggggaaagc tatgaagctctaggctttgtcttgttcaagtaaaaggttaaatttttcattaaggtctgt tgattcccatgcgatccttctcaccttgcttaattctgataccaatcttttcttaatttt aggcatacagagccaacagtaattatttttaagttactttcaattagttttcagttgtaa ttttgtcacctttgtttttaatcatgtaggcattggggcatgteggtctgatctggagaa aaaaaattctctaggatcaaagacaggacagtcacttgatttctctggcatatgagaagt gctgttcctcaagccaaacatttaattgttggaattttatgttggagcaagtaaagatct taagcttacttcatctgtttaaagagatttaagacaactgccctttttccttgtactcaa aaccagtcttagtgatttgttttactgtggaaaaactggtttgcttaatctaactaaaca ttttagaatgagtagtaattttgtaaccatcatgccacactcctctttctcataaattct tgtgtaacaaaagtgtgggacagggaatgacaaatgtgactttatttttttaacaaatgt aagttttcagttcttttttttaaatttttaattaacagataataattgtatatgttcgtg ggatacagtgtgatgtttcaatacatgtatatgttgtggaatgaaaaaatcagggtaatt aacacatctattacctcaaatacttatttctttgtggtgaggacatttaaaatccactet ttttgttattttgaaatacacaatacattattatgaattgtagtcaccatgctatgcaat agatcaccagaacttactactcctgtctaaccacaaccttgtaccctttaactggcacct cctttctctatetaacccactccctccagcctctggtactctctacgtgtatgagttcaa cttttttagattccatatatcatgtggtgtttgcctttgtatgcctggcttatgcttatt tcacttagcataatgtcctctaggttcatccatgttgttgaatatgacataattttctgc _._ ... _.. ttgaggctgagtagtattccattgtgtgtatatgccatatttatttcatetgtttatcca---ttgatgggcatttcaattgtttccatatettagctattgtgaatgatgcagatgctacag cgtagttcacctttgttttgagagagggagagagagagacagagacagagagagagagag aaaaggcctcactctgttactcaggctggagtgtactgatgcaattatagctcactgcag cctcaaacctatgggcttttgagatcctcccatcgcagcctcttagctacaggtgtgtac caccatgcctagctactttaaaaaaaattcttttggctgggtgcagtggctcacacctgt aatctcagcacttggggaggctgaggcaggaggatcacctgaggtcgggccaacatggag aaaccctgtctctactaaaagtacaaaattagctgggcgtggtagtgcatgcctgtaatc ccagctacttgggaggctaaggtaggagaattgcttgaacccgagagatggaggttgcgg tgagccgagatcgtgecattgcactctagcctgggcaacaatagcaaaactccgtctcaa aaaaattttttttgtagagacagggtcttgttacattgttgcccaggctggtcttgaact cctggccttagccaggagttgaattcaaccaactctttggetgaatgtgtagccaatgct acttcacctatttagatagctgtattatggctccaaagctgaaaactgaaaaattaatat taacagccaggcatagggctcatgcctgtaattccagcactttgggaggctgaggcaaga ggattgcttagcccaggaggttgaggctgcagtgagccaagattgcaccactgcactcta gcctggaccacagagtgagaccccatctcaaaagaaaaaagaaaaagaaaagacaagaaa agaaaaaattaacagcacttagaaaaggaaagctaagtacetccaagcatatctagtttt gtaacttatatagttttcctttataatgttaaaacattataatgttataatgtaaagaac ttatacattatgaattattatacattattacattatttataatgtaatgtaaagaacttc ctttaacatttcttttgtttttgttttgttttgttttgagatggatccttgctctgtcgc ccaggctggggtgcagtggtgtgatctcggctcactgcaacctcgacctcctgggttcaa gcgattgtcctgcctcaacctcccgagtagctgggattacagacacctgccaccatgccc ggctaatttttgtatttttagtagagatggggttttgcagtgttggccaggetggtctcg aactccagacgtcaggtgatccgcctgcctcagcctcccaaagtgctgggattacaggag tgagccactgcgcccggcctcttgaacatttcttatagagaagttctgctggtgagaaat tattcatgtttttaatttcacttaaaaatagatttattgaggtataattgacatatatat gtatacataatatatataataagttatacatattaaaactttacagttggatgagttttg atacctaggaacccatcagcacaagcaaggtagagaacgtatctgttatccccaaatgtt tccttgtgctaagcagtgcctcactcctgctcttttgtectcaggctactactaatctgc tttctgttactacagattagtttgcattttttagaattttatatggatagaatcatcata tagcatgtactttttggtgggatgtgtgtatcagtagttcattcettcttattgctgagt agtattctatcctgtggatgtactacaattcattaatctgttgaagatcattgggattgt ttttggttttggctgttttaaataaaggtgctatgaacagtcatgtacaagtccttcctt gtatggaaatatatttccatttttcttgagtcaaacctagaaatagaatagctggatcat gtggtaggtatatatgctgcttttataaaatggaaaaagaagattttgaaaaggagatga gatggggcacttcatcccaggcacatccttgggcagatggtttttagtaaggaattcaca aggaagttgaggatcaggaaattgattccttttaaaaactgtctatgcctgttagtccct gaaaagttttcctgcactccaggggtactgtattccaattagaagatagctgacttagag atgtccccagctacttctcttagttctggcctctgccccagctctgttcttcagacggac cttatgcccaggaaattctggctgccatcttttacacaccaggctgtctggaggcctggg agaaaaaggaattagactggggttcacctgggagaaacccttggcagtggtggagtgggg atggattcagaagtgaggtatgatactataatataatgaaaaaatgtatctgctattcat cgctggttcctgacagtgcctaaaacccttgttcaagtaaaaggttaaatttttcattaa ggtctgttgattcccatgagatcctgagtaatagaagtgagaagagcatcttttgttatt tatgataagcccctgccaaccaaacctgattttatgctaatgaggtggctcttggaggat ggcttctggttgccagaggaatcaaccatgtggttatetctaaggtgggacttttcagcc tacctcccccttatttctgaggagggcagaggggcctggagatggagttaatcaccagca gccagtggtttaatcagtcttgcttaggtaatgggacccccttaagaactcaaaatgtag gggttcagagagcttcctgctcggtgaacaaatcaaggtcctgggagggtggtacatctg gacccggcttggaagctctgtgtccccccgtaccttgtcccattacctcttcatctggct gttcatttgtatcctttataatatcctttataataaagtgtttttgtagcaaattgttta acatgaggagggggttgtgggtgtaggggccagggaaaagcttccccattgatctccaaa ggtttgctgaaaaatcaactcacaagaggcagattaattggagaaaagtcatacagattt tattacatgtacacgggggaaccacagagattactcaccccccaatggggttcggaagca tgtataatatcctggcaaaacaggttatatggetggtccaggtgcagtggtgtttacagc taattgatcacagccagttacagatttctttgttccttccactcccactgcttcacttga ctagcctaaaaaattaattaattaaataaaacaggttataggagaagggagaagaggaat tctgttgtgaggattactaggaagaatgaatggatcagggaagggagattaacttgtaca ttatcttgtggaaggatctgttcaggtgtgattacattcttggtcttactgggaggggaa tgcaaaacagttgttctcggtgggtctggattttaggcgataaaggaacttcagagaacg tcattctgactttgggagaagtcagttgtaggggtgggtggttgggggaagtcagagaga ' ccctgaggtattggttactgagtcccaacatgggaatgcccagtttgtagccaagtcaga ctaatttgactgatttgtggctaatttgaggatccactacttgcaattagcatctgaagt tgggggtagtctgtgggactgagccctaaacctacgggggtctgtgctaactccaggtgg tgtcagaatttaattaaattgtaggacgctcgattggtctccacagagaatagatttgct tctggaaaactcacacatctggtgtcggaagcattgtgagtggagaaacagttttttatt tatgaggcaagagaggctatgggggtcttgaggcggtattggggaccttagatgctatca tctgctccagtatctgggaaggtctgtcctcctcattggcatcccgtctccagttgccct gtcttcttcctctccctcatagaccactgttcacacgggatacacttatgatecccacac tgttttctcettactctcacttctccatccctaggcaatcactgatctgctttctgtcac tattccatacatat~.aatgacaaaatatagtgggtttttttgtttttgaaagacaggatc tcactgtgttgctcaggttggcctccaactcctgggctcaagcagtectcctagctgaaa ctacagatgcacaccatgactcctggctcaagcacagtgtttttgtactttttaataaat gacattatatatcccatattctgaaatgtctcttttttccctggatgttatgtctttgtt tttttttttttttttttttctgacacaaatcctttctttgtcacccaggctggaatgcag tggtgtgatcatggctcactgcagcctacctctcaggctaaagcagtccccctgcctcag cctcccgagtagctggaactacaggagtgctccaccacgcccagctaattttttttcttt tttttctttttgagacagagtctcgctcttgtcacccaggctgtagtgctcgctcttgcc gcccaggctggagtgcagtggcatgatcttagcccactgcaacctccgcctcccgtgttc aagtgattctcttgcctcagcctcctgagtagctgggattacaggcgcctgccaccatgc ccagctaatttttgtacttttagtggaaacagggttttgccatgttggccaggctggtct tgaactcctgacctcaagtgatccgcccgcctcggcctcctaaagtgctgggattagagg gctgagccactgggcccagcctaaattttttattttattttttgtagagacagagtcttg ctatgttgcccaggctggtctcaaaactcctaagcccaagtgatcctcccgctttgctct cccaaagtgttaggattacaggcatgagccaccatgcccagcagatgtcttgagatctgt taatgtagttagagaactagtgtaccctttaaaaatttttttattgtaattaaatataaa taagaaaatttaccagttcgaccactcttaagtgtacagttcagtggtataagcacattc acagtgttgtacaactattaacagtatccttctgtttccagaacttttcaccatcccaat cagaaactgtacccattaaacaataactccctatccctccttttgcagtccctagtaacc tgtattaaactttctgtctatgaatttacctatgcttggtcacctttgtttttgtgtttt tgaaagatgattgtgattggtaaataactccaggttggaagtttttgtttttttttctcg ttcagtaccctgtcttatagcttgcattgtttctgatgcaaaatctgctatcaacttcct ttctgtatgtgaagcatctctttggctgcttttaagacttttttgttttgttttgttttg gagacagagtctttgcctggagtgcagtggtacagtcatggctcactgcagccttgacct cccaggctcaagcagtcctcecacctcagcctcccaagtaggtgtgcgccaccatgceca gctacttttttagttttttttttaaatagagatgggatcttgctatgttgcccaggctgg tcttgaactcttggactcaagcaatcctcccaccttggcctcccaaagtgctgggattac aggcgtgagecactgcagctagccttaaaccactgtttaatccagtgttttaaaattgtt ttagagggagggttatgtctattcctattacttcatctctcctgatgtgaatgttgaggc tggatgcggtggctcacacctgtaatcccagcactttgggaggcagaggcgggcggatca cctgaggtcgggagttcgagaccagcctgaccaacatggagaaatgccgtctctactaaa aatacaaaattagctgggtgtggtggtgcatgcctgcaatcccaactatttgggaggctg aggcagaagaatcacttgaacctgggaggtggaggttgcagtgagccaagatcgtgccat tgcactccagcctgggcaacaagagcaaaactctgtctcaaaaaaaaaaaaaaaaaaaaa aaaaaaaaagttgaggatgagcggcttcatgggatggcatgtatttctgtaaccactgac ttccacctcccagaaaaaggaagcaacaagccaaaaattcactactgttgttattgggcc tgatagtgaaaggatgaccacctaaaaattatggcatccttggaaaatttttgcaaatct gtattttaagcagtgtaaccctttacagtaagggagtacagtgacttttgcaagtggttt agtgttctgactgcatatccagaggcaggatggcagtacgaaggtcctagtgggaacaga gagtgagagtctgtgagtctgtggctaactcagacatcagggagaagaatgtgtgatact gtctcagaggttgccaactttggtattaggctgtgttctttgaaatgtggggcactgaat ttaggcatatactgaaataactaaataaaacaagagttacatatatgtttcatgttctac atcctgtcaggttatctcatataaataattggattgtgaatatttacctaactttttgag gtctaatgccctaatttgctgctttctttttgtaggtaaagaacaacagcagcaacaaaa acaaaaacagtagatatattgggggggggaaaaaacctgctggttaatatacagatttca ttaccttgaagttcactgcactgaacaattctcactctggatgtattcctgctctaggat gtgaatttagacttttgtaatagagtgggctttgagaaatagcttttctgctcattttag tttcatgatgactgcatggaatgttttgcttcacgcttatgcattgagttttatcaagca ttaagcagttggccgaaacaggtaatacttgaacattcagtccaagaaaaacaaaatgga tttgaacatacgtagaatcagtaactcttattttcatacttccttatggttattcagaag tgttggtctctaggtacattttgaaagcaagtacttgatctggcttaggttttaactaac agcaagcagatactggcctgataaaaagatgatgtacagcaaaagtgagatggtcagaat tggcttttttctttttcttttcttttttttttttgagagggagtcttgctttgtcaccca ggctgtagtgcagtggcatgatctcagttcactgcaagctccacctcccaggttcatgcc attctcctgcctcagcctcctttgtagctgggactacaggtgcecgccgccacgcttggc taatttttttgtattttcagtagagacggggtttcaccatgttatccaggatggtctcga tctcctgacctcgtgatctgcccacctcggtctcccaaagcgctgggattacaggcatga gctaccgcgcceggccagaattggcttttttcattatagactactacagtaaaatcatcc taactgcagaagtcacttgaaatgtggaaatcacagtttgctatgtatttgatttggttc aatctttttttttgctttctgggacatcaaaatcagccagcgagtctagggaaatttgga cttaaggttttaatgtttagattttgaaaagccaggatgcttataaaacactcattggta tcatttacgacagagagagagagagaaaggagagagagagagagtgcgtgtgtgcgttta tgtgtgtatgtatatcttgtttaaaaaacagtctggactcagttttctcacctggaacat tagaaatgaagtgttagctgggcgtggtggctcacgcctgtaatcccagcacttttggag accaaggtgagacgattgcttgagcctaggagtttaagaccagcctggtcaacataggga gacgctgtttetacaaaaaaagaaaggaaaaaaagccaggcatggtggcatgagcctgtg ggattcagctcccaccttggaaggctgaagtaggaggatggcttgagcctgggaggtcaa ggctgcagtgaaccaagatcatgccactgcattccagcttagacaacagagtgagactct gtctcagaaaaaaaaaaaaaaatgataccaactttcatatttgtggcaaaatgagataaa tttacgtaactgaaaaagggagtctttttttaatgaattactttatttctttgaggaaaa ataaaacagatttgtaaactttgctcctggactagaatgctactttgcaggcaaacttac ttttgtaaaaatgctagactctggccagacatggtggctcacacccataatcccagcact ttgggaggcetaggccggtggatcacctgaggtcagcagtttgagaccagcctggcctct gtcgctattaaaaaaatacaaaaacaaaaaaattagctggacgtggtggcacacacctgt aatcccagctactagggaggttgaggcaggagaatcacttgaacetgggagctggaggtt gcagtgagccgaggtgtcaccaccacactccagcctgggtgacagagtgagacttggtct gaaaaaaaaaaaaagctagactccacattctttaaaaaaaaaaaacaactttgctaagat ataattcaccaatgtaaagtgtacaattcattggtttttagtataatcacagagttgtgc agctgttatcaccatcaattatagaacattttcattaccaaccccccccccccaaaaaaa aatctcgtgtctattagcagttgctacttgtttcccccctacccctttctetgcaggccc cagacctagacaaccactaatccacgatatgtttctacagatagactgattctagacatt tcctatacagtgtcattactaattccttttatgggtggataatattccattgtatggata tacatattttatttatccatttatcaattgatggacaattggctattgtgagtaatgttg ctacgaacatttggttacaactttttgtgtgaatatgttttcatttcatatggtaactgt ttaaccttgtgaggaactgccagttttccagagtggctacaccatttaccttcctaccag cagtgtatgagaattccaatttctctatatacacttagacttgttatttatcagtgtact gagttttgatcaaaaatagtgtacctgtgtagtgtggttaaatcatgttgacctcactct ctttcatctagcctcttaaaatatcaatactaagacttataaaatgagcatatgaaaacc agtaactttccttcctacagattgaaaatactcaatcagaaagtatattcaaagaaaata tttaatccacagtagcgacataaaaataggttttaaaaaaaatctagtaataaaccttag agaaatttgaagaaactatataaagaaacaagaaactcaattgagtgtcataaaacgaaa cttgaatgaatggtttgggaaaaagcaacattatacaaagtgaattccctgcatatcaat ctgtgaagaaaacatttctcccaaatttccaacaggattttaaatctgacaaaaatttca tcaggaaaaataaatgctcaacaataaacaggaaaattttgaaaaagaaagtttggaaag agaagacttttcctaatgttgtatacaggaatagtaacaactgagagaaaatatttgcaa catttacaacaaaggattactatctctattgtacaataaatgecaagaagaaatagatga aaaatctacataatgaggtataaatagtcaattcataaataacaggctcaaaaatcacta ataattaaagaagttttgaaatattaaagtgagacattacttttcacctattggactgga aaatacagaatttagtaattatctctaagaaattagggccaggtgtggtggctcacacct gtaatcccagcactttgggagaccaaaacaggtggatcacttgaggtcaggagttcaaga ccagccaggccaacatggtgaaaccctgtctctactaaaaatacaaaaactagctgggca tggtggtgggcgcctgtagtcctagctactcaggaggctgaggcagaagaattgcttgaa cccaggaagtggaggttgcagtgagccgagatcacgccactgcactccagcctgggcaac aacaagactgtctcaaaaaaaaaaaagaaattaggaaagattggccgggtgcggtggctc acgcctgtaatcccagcactttgggaggccgaggtgggtggatcctgaggtcaggagatc gataccatcctggctaacacagagaaaccctgtctctactaaaaatacaaaaattagcca ggcgtggcggcgtgtgcctgtagtcccagctgctggggaggetgaggcaggaaaatggca tgaacttgggaggcggagcttgcagtgagccgagattgcgccactgccctccagcctggg tgacagagcgagactccgtctcaaaaaaaaaaaaaagaaattaggaaagataccctgttg gttgaatgaatgtatgtgtcataactcttttggaggacagttggaaatacttggccaaat tttaaatgggcagacttttttttgttaattttttactt aattttaatggatacatagta_.... ..._ ggtgtatgtgtttatggggtacatgagctattttgatgcaggcatacagtgcataatcat gttgcgtaaatgggatattcatcacctcaagcatttatcatttatttgtgttacaaatat tccaattatactcttttagttatttttaaatatacaataaattttgttgactgtaattac cctgttgtgctatcaagtactagatcttttttttcttttttactttttctaacctttttt tttttctgagacagtgtctcactcttgctcaggctggagtatagtagcatgatcacagct cactgcagccttgacctcccatgctcaagcagtcctcctgcctcagcctactgagactac aggcttgagccaccattcctggctgttttttaaaattttttgtagagatggaggtctcac tgtgttgcccggggtggtcttgaaccaaatactagatcttactcattctgtgtgagtata gttttgtacccactctccaccactategttcccagcttctggtagctatcattctactct ctatctccatgagttcaactgttttaatttttagcttccacaaatgagtgagaacataag gtttgtctttctgtatctggcttatttcacttgacacaatgtcttccagtttcatccatg ttgttgcaagtgacaggatctcattcttttttgtggctgaatagtactcccattgtattg ctagacacttaagttgcttccaaatcatggctattgtgaatagtgctgcaataaatatgg gagtgtacatatctcttcaatatactgatttcctttcttttgggtgtatatetagtggtg ggatttctggatcatatggtaggtgtgtgtttagttttctgagaaatctctatactgttc tccatagtgactgtactaaagtacattcccaccaacagcatgtgagggttcccttttctg catatcetttccagcatttgttattgcctctcttttgga~aaaaaccattttaactggaa tgagatgatatcttgatgtagttttgatttgcagttccctgatgatcaatgatgttgaac accctttcatatacctgtttgccgtttgtatgtctccttttaaaaatgtctgttcaggag ccgggcacagtggctcacgcctgtaatcccagcactttgggaggttgaggtgggcagatc ttgaggtcaggaaatcgagaccatcctggctaacatggtgaaaccccgtctetactaaaa atccaaaaaattagecgggcgtggtggcaggtgcctatagtcccagctactcaggaggct gaggcaagagaatggcatgaacctgggaggcagagcttgcagtgagccgagatcgtgcca ctgcactccagcctgggcgacagagcaagactccatctaaaataaaaaaaaatgtctatt cagggetagggatggtgtctcacgcttgtaatcccaccactttgggaggccgaggcgggc ggatcacttgaggtcaggagttccagaccagccaggccaacatggtgaaaccctgtctct actaaaactacaaaaattagctgggcatggtggcacgtgcctgcaatcccagctacttgg gaggccgaggcagtagaactacttgaacccaggaggcagaggttgcagtgagccaagatt acgccactgcactccagcetgggtgacagagcaagatccgtttccaaaaaaaaaaaagga aaaatgtctattcatatcttttgcccattatttaatcagattattaggttttttttttcc tattgagttgtttgaact.ccttgtctattctggttattaatcctttgtcagatgcatagt gtgcaaatattttctcccattctgtgggttgtctcttcatttttttgattgctttgtttt gcagaaacctaagttgatgtgatcccacttacetatttttgctttgattacctgtgattg cggggtgcaactcaagaattacttgcctggaccagtgtcatggagagtttccacagtttt ttcttttagtagttgcatagtttgaggttttggatttaagtctttaattcattttgattt gatttttgtatatggcgagaaataggggtctagtttcattcattcttctgcatgtggata 6~

tcttgttttcecagcactatttattgacagtcttatttattgaaggetgtcttttcecca gtgttatgttcttggcacctttgtaaaaaatgagttcactctagatgtatggatttattt ctgggttctctcttctgttccatcggtttatgtgtctgtttttatgccagcaccatcctg ctttggttactacagtttgtagtataatttaaaggcatagaatgtgatccctccagtttt gttctttttgttcaggctagctttggccattctgggtcttttgtggttccatataaattt acaatgatttttttctatttctgtgaagaatgttattggtattttgatagggattacact gaatctgtagattgctttcagtagtatggacattttaacagtattgattcttccaatcca tgaacatggaatatctttccttttttttttttaatgtgtatgtcttcttcagtttcttgt atcagtattttatgattttcattgtaaagaaagagatctttcactttttttttttttttt ttttttgagacagagtttcacttttgttgcccaggctggagtgcaatggcacgatctcag ctcactgcaacctccacctcccgggttcaagtggttctcctgcctcagtctcccgagtag ctgggattacagggatgcaccaccatgcctggctaattttgtatttttagtggagacgag gtttctecatgttagtcaggctggtctcgaactcctgacctcaggtgatcctcccacctc ggcctcccaaagtgcagggattacaggtgtgagccaccgcgectggctgagatetttcac ttcttttgtgatacttattcataggtatttttttatttgcagttactgtaaatggaatta cttttttgattactttttcagattatttgctgtggcatatagaaatgctactgatttttg tgtggtgatttcatatccttcgactttactgaattagtttatctgttetaatagtttttt tgtggagtctttaggtttttecaaatatataagatgatatcatetgcaaacaaggataat ttgacttcttcttttctaatttggatgccctttatttctttctcttgtctcattgctcta gcttggacttccattactatgttgaataatagtggtgaaagtgggcatccttgtcttgtt ccaaatettagagaaagactttcaattttctcccattcagtatgatactaggtgtgggtc tgtcttatatggcttttatcgtgttgaggtatgttccttctatccccagttttttttgga tttttgtcatgaagggatgttgaattttaccaaatgctttttttagcatcaattgaaatg _. atagtatgatttttgtcctttattctgttgtatcatgttttattct.gttctatcatgtga ._ tatatcacgttgattgatttgcatgtgttgaaccatccttgcatccctggaacaaattcc agttggtcatgatgaatgatctttttaatgtgttgttgaattcagtttgctagtgttttg ttgaggatttttgcatcaatgttcatcagagatattgacctgtagttttctctctttttg acatatttgtctggttttagtaatactgatgagtattactgggtcttagaatgagtttga aactattccctcctcctccatattttggaatattttgagtaggattggtattagtttttc tttaaatggcactgaagccattggatcctgggcttttctttgetgagagactttttatta tggcttcgatctcattacttgttagtactctagtcaggctttggatttcttcatggttca atcttggtaggttgtatgtgtctaggaatttatccatttcttctaggctttctgatttgt tggcatatagttgctcatcgtagcctctaatgatcctttgagtttctgcagtattagttg tattgtctcctttttcatctgtgatttgatttctttgggtcttgtatcttttatttttag tccggttaaaggtttgttgatactatttgtcttttcaaaaaaatcaagtttacattttgt tgatcttttgtgtgttttgtttcaatttcattcatttctgccccgatctttattacttct tttcttctactaattttgtgtttggtttgctctcgcttttcttgttctttaagatgcatc attagtttgttcatttagcgcctttctcctttttttgatgtgggcacttattgcttgcta taaactcacctcttagtactgctttcactgtatcccattggttttggtagtagttgtgtt tctattttcatttttttcaagaaatttttcaatttttttcttaattttgtattgaccccc tgettaataaggggcatattgttaactttcatgtgtttttgtagttcccaaagtccatct tgttactgatttctagttttgttccattgtggtcagagaagatacttgttagtttttgta ggttagtaacaatatttggattatactaaggagtttttatctagagttatagagattttc ttagaatgctgccatggtagagaataagtgggtgggtatataggggaaaacaacattttg aaatatgtttcaaattttccagattaaacagttaaaaagaacaggtggtgaacctagaga atagtgttttagaaaccgagacacaggatttcttaatagtgggcaactttgtcagggact gcaagagagatcacctagaataaggactgaaaagatgtcataggtttcagcagctggttt catgacctttgcaaccgcagttttggtggagtgtttgggctaaaacctggcagcagcatt ttgagaaatgtgtggaaggtaagaacatggagaaaggatatgatcactatgtgaaaaaaa gttgtttcattataaaagattacaaacttatgatttttaaaatattaaagagaagtatga agtgaaaaaaaaccctgccccttttcctttctcatcttctcacctgtttcctccagtttt agtctctagttttactcttgagatttgtggctactgaatgaatggagtgtcaatetgaat gggaaagagaatttttttttttttttttttgagacaaagtctcgctcttgttgcccaggc tggagtgcaatggtgtgatctcggttcgctgcaacctccgcetcccaggttcaagcgatt cgcctgccttagcctcctgagtagctgggacaacaggcacgtgccaccacgcccagctaa tttttgtgttttcgtagagaeggggtttcaccatgttggccaggctggtctcaaactcct gacctcaggcgatccacccaccttggcctcccaaagtgccgggattccaggtgtgagcca ctgcacctggcctgaaagaggtttttgagagggagactcagaaacgcctttgcctgagaa gagctaggaaatagaaggaaagaaaaaaatggaacagaggagctcagagaagataaaagg aagtagggatgcagtggtcaagtgggagaaaaaaaaggagaggcactcttttctttgagt agccaggaaaaaatgactttgtttttctttctcaattagcagaccaagctgtatgctggt gattgaggtttggatagggttggtggcatctagtgtgtagtaactatgggaattagcaaa tcaatggcagagtgaaggactcactttcactcgctcaggtccaaactaggctttaaatga cttcttttttttttgagacagtcttgctttgttgcccagggtggagttcagtagcacaat cttgactcactacaccctctgcttcctaggttcaagcgattcttetgccttagcctcccg agtagetgggactgcaggcacacaccactgtgectggetaatttttgtatttttagtgga gatgggctttcatcatgttggccaggctggtctcgaactcctgacetcaacccgcctgcc tcggcctcgcaaactgttgggattacaggccaccacacctggc,ctgaatgactttttcac tgaggaatgccatagtccaggcagatgtgccacctcattgatcgccagggatgactcagt tgtctggctagttgggtaagggaggtgttttttccatcacttctgtgtgtetgttactaa aactgttcatttatatttcacagcagctcaagtgcaactgttcttcagtacttttgtagc ttttcatttctgtgactcctttgaggaggctctgtcatgtgaaaggaaaaatttgataaa atgattacatggagacttctaactaatcgtattgtggcaatggaactactttcacttcct cttttaaagaaacaggtaacagaaagectectctttagactttcccattagacacatagc agtgacaatttaaactgtggtcagtagccaggcatggtggtgcacttctgtagtcccagc tatttggaaggctgaggcaggagaatcgcttgaacccaggaggcggaggttgcagtgggc caagataacaccattgcactccagcctgggcaacaagagccaaactccatctcaaaaaaa aagaaaaaaaatgtggtcaggaatagattctgtttgctgtatttgggatatatacaatgt taagaacaaaatggccaggtgtggtggctcatgcecataattccagcactttgggaggcc caggcgggaggattgcttgagcccaggaggtcgaggctgtagtgagccgtgatcatgtca ctgcattcagccttgagtgacagagtgagaccctgtctcaccaaaaaagaaaaccaaaga acaaaattttatatctatatacattggtgtctgtgaacctcatgtggtatttttatgcaa atagaaatggaagttatatgttacctacttcagaaaattgaattgtctaaataaatatct aaatatttgtcct.taggccaggcacg~tgcttcacgcctataatcccagcacttt,gggag _ _ ., gccgaggcaggcggatcacctgaggtcaggagttcaagaccagcctggacaacatggtga aaccctgtctctactaatacaaaaattagctgggtgtggtggcacacacctgtaatccca gctactcgggaagctgaggcaggagaatcgcttgaacctgggaggcagaggttgcagtga gccaggatcatgccactgcactccagcctgggtggcaagagcaaaactctgtctccaaat aataataataataagtaaataaatatttgtccttgtcatatatttgtttataaatatgag attattttttctaaaaatttacattatgaaatttgtttagtaatcatcacatttaggggt tttaaagtgacctttactttacttttgtgttttttagGAGACCCGTGTACAGTATCATCT
CAGTTGGAGTTAGAAGAAGCCTTTAGACTTTATGAGCTAAACAAGGATTCTGAACTCTTG
ATTCATGgtaagagagtagtcatttcatactcgtccagactgataatttctttgaaatca ctctttattcttcaccattttgaaacataatcttaatgtcattttctcaatctctgtgac tcatgcctaagtaattgtcgttatttagtagtttctcacgtgctacagaaggtaaaatta atctgctgcttatagtctggggaattttgtggtctctgtatgtcttgttggatattaaaa tgtgatatctcagtgtatcacagcaaatttatgatagaacttaaaaattgagagcctggg gaatctaagtcatctacttgaaattttgttatgtatacaaataatgacctccaaaggtaa ggtatcttaaatatcctttcttttgcttaaaggttaatagtgaaactatttacatgattc ctttatttttgagacagtctcactctgtcacccaggttggagtacagtggtatgatctcg gcccactgcaacctctgcctcctgggttcaagcatctcagcctcccaagtagctgggatt acaggtgtgcaccaccatggetggctaatttttatatttgtagtagagacagggtttcac catgttggccaggctggtctcgaactcctggcctcaagagatccgcctgecttggtctcc caaagcactgagattacaggcatgagccactgcaccaggcccatttacatgatgctttag agacattaatatgtttatacctcagcaaccttgagatgtaggaagtggcatagaagaagt aacctaaactcagttatcattgtaactggcacgttgtagacctggattgtgaatctagga attctgattccaaatttgtgtttcattcaactatgctaaccatcaaaagtcatgtaaaac tttttttttgtttgtttttttgaggcagtttctctcgctctgttgcccaggctggagtgc attggtgcagtcatagctcactgcagccttgacttcccaggttcaagegatcctcccacc tcagcctcctgagtaactgagaccacaggcactgccgcaccactatgactggctaatttt ttttttttttttttgtatagatcggatatcactatgatgcecaggctggtetcaaactcc tgtgctcaaagagtcctaccacctgggectcccaaagtgctgggattagaggtgtgaacc accatgcccagccaagaacctcttaatatactgcatttaattgcaatatattgacagtat ttcgttgaacatttttgagagctatgagaccagacttaggaatcttetaaaaaagtgaaa cgaatgtaaatctttccttaagtataatgaatcatttcagtgccttattattatttcttt gtattttcctttacagtgttttttttttaaaaaaaaaaaaaaaacagtggtttgatttta tattttatttgagacacagtttcactctgttgcccaggctagagggcagtggcacagtct caactcactgcaaccttggcctcctgtgttcaagtgattctcatgcctcagcctccaaag tacttgggattacaggcgcctaccaccatgcccagctaatttttgtatttttagtagaga tggggtttcaccatgttggccaggctggtctcgaactcctgacctcaggtgatctgcctg ccttggccteccaaagttctgggattacaggcgtcagccactacgcctgacctgattttt ttctacctccagaatttgacatagtgactcacaagggatccataatgtactttgttgaga ttctaaaagagctttaagagtetattttttttgtcatctctttccagaataaaattacaa tgaatgcataaagaagtgattgatgaatggtattaaacagtcagttttaagtcttattgc cttttaatactacatcacagatgttttcagaagctagcttacgtttcagcttttaaaaat atgcattaggaactgtgcttcctatagtctgtgctctttattaaactgtgtcctttagta catcacagactaagaatagctgactagatattcataaatacattgttgctttatattcta ccttgttataaaaatggttttaattagtatatacatttaaagtttctaatgtaaatttac atttttgattttggtactgtttctggtgttaatttattcctaagtttagtatacatcttt taaaaaccaatatti-.tatgttccatatttgtatacatttttgtaatttaattttcatcct tcattgtgacaaacttgtcctactataccaaggatttaaggcgatattagttaatgattt ctttaaggataagaaaataattcatgatgtaacagggactggaattagtcatttgagctt ctgatgcattggtttttttgttttgttttgtttttgtttttgtttctgagatggtgtctc attctgtcacctgggetggagtgcagtggcatgatctcagcttactgcaaccttcgcctc ccaggttcaagtgattcccgggcctcagcctcctagggagctgggattacaggcacatca ccatgccaggctaattttttttgtattttttggtagagacagagttttaccatgttggcc aggctggcatcccctgacctcaagtcatccacccaccttggcctcccagagtgctgagat tagaggcgtaagccaacgtgcccagcctaatgcattgtttatagacatgtttgttttcat aagaacttttttctttctttcttttttttttttttttttaacatcaacaaagcaaggcaa ataaaaccttcttttgtggccgggcgcggtgactcacgcctgtaatcccagcactttggg aggccgagacaggcggatcatgaggtcaggagatcgagaccatcctggctaacacggtga aaccccgtctctactaaaaatacaaaaattagccgggcatggtggcgegtgcctgtagtc ccagctacacgggaggctgaggcaggagaatggcgtgaacccgggaggcggagettgcag tgagtcgagatcgcgccactgcactccagcctgggcgacagagcgaaactctgtctcaaa _ _. __ aaaaaaaaaaaaccttcttttatatggccttggtaaaatgaatccctttggcaaataata ttgatcacatgetaagtatcttgtctcaagtgaagagagggtcaggttgaaatctgggtc agtttcttttacatttgaattttaaattctgtgtaatttgtatgttttaaatatgctgtt aactcatgttcgtttattttctttcagTGTTCCCTTGTGTACCAGAACGTCCTGGGATGC
CTTGTCCAGGAGAAGATAgtgagtgtttatatactteataccttttacaagagttactat gctatggtacaagtgaaaaagaaatcagagatagaatttttagctaggtgcagtggacag tggctaatgcctgtaatcccagcactgtgggaagctgaggtgggaggatcgcttaagccc aggagttcaagaccagcctgggcaacaaagtgagaccttgtctttccaaaaacacacaaa aaaattagcatggtgtgtgcctataatctcagctacttgggaggttgaggtgggaggatc ccttgagcccaggaatttgaggctacagtgagccaaggtcgcactacttgcactctagtg tgggtgacagagacaggccttgtctcaaggggaaaaaaaaaaaggaaatagaagttctaa ttcatttgatttcttttccatttttcagtcaatttagaatatattagtgactgcccaaat gctactttgccagatcaaattcagatagttcttagttacaacttacatgattgcctgttg cacatatgaaaggaatattaagttaaatttaagttttaaaattcaattttggaaatgttc aaacctatacagaagttgaaacaacatggaaaacaaggatacctatatatcctttgccca gatttaccaatttttaacgttttccctgtttgctttatctctgt~.tetgtctatatctca tatatgcatgcacagttatacataacaaacacatttttttttttttggttataccacttg agactgacatgacactcagcacatgtaattaggaattggctttttttttttctgcagtgt tttttacttaaacaggtattaagtcacttttgttgttgttgtttttgagacagaatctcg ctttctcacccaggctggagtgcagtgacgcaatcttggcteattgcaaccttcacctct ggggttcaagcaattctcctgcctcagcctcetgagtacctgggattacaggcgccaaca ccatgctcagcttatttttgtacttttagtagagttgaggtttcaccatgttggccaggc cggtgtcgaactactgacetcaggtgatccacctgcctcagcctcccagagtgctgtgat tacaggtgtgagccactgcacctggccccaagtcacttattaaatgtctttaaatattgc agacttcctacagttgacccagagaaatgtgtatatttattagatctccaattcctagta acttcaggtaaccaaccagagtccacagtggaacggtgattcttacecttggacacatta aaattgtgggatggagggaatgatcaatgccaaatttccatccccaagcttaatgaatta gtgtggaggtgaaatctggatatctttgtattttaaaatggactctcaaaatgtagccat tgggtcccacagcatcagcttcacctgagaactgaatagaaactgcactecaggctgggt gcagtggctcatgcctgtaaccctagcactttgggaggctgaggcaggcagatcacctga ggtcaggagttcaagaccagcctggccaacatggtgaaagcccatctctactaaaaatac taaaaaagttagctgggtgtggtggtgcatacctgtaatcctagctacctgggaggctga ggcaggagaattgcttgaacctgggaagcggaggttgcagtgagctgaggtcgcgccagt acattccaatctgga.caacagagcgagactctgtctcaaaaaaaaaaaaaagaaaaaaac tgcactccaatctacgtgattcataaactcttggactggggctgagctaccagatttaac aagctcttcaggtgattctgatgcacactaaagtttgagaaccaccatttaaaagcttcc ccaggtcaggaattgttaacggaatttctttggaatatctaagccaatggttactattaa tgagatgaactaagagtgtccaactactctttgttctaatgtaatttaatatgcaaactt atgtttgattgtaagttattgcttttggtattttggcataatttactaattgtggatatt aggcaactcattttcatttgtggtttctgcacatgcccatcactttagaaggaatagtgg taaatgctttgctttgaattaatcgaaatagctctaaactttctttttcttttttttttt tttgagatggtcttgctctgtcgcccaggctggagtgcagtggcgagaactcggctgact gcaagctctgcctcctgggttcatgecattcagcctcctgagtagctgggattttaggtg cccactaccacgcccgtctaatttttttttttgtatttttagtagagatggggttttgta tttttagtagagtgctagccaggatggtctcaatctcctgatcttgtgatctgcccacct cggcctcccaaagtgctgggattacgggcgtgagccaccgcgcccggcctaaactttcaa ttctgtattaagctatcctgagatttctaattgagagcattgcaactggtctttagtatc ttaattttaaatagtaaacccattgctatatttgctttaaaatatgactttgggaacctg ttgtaatctttctatggtattaactattactgttattaccattactgtgggatgttatta ttaatgactaatagacaatatataaaataatgatggacttaaaaatatgaaggtggacta gatttgatcgtttggaacetctttctctaactatatttgagaaacatattaatataaaga ccactggatgaaaagttgttggggaaaaagatatgcttctggtacaaaatatcactttac agattagttacaaagactgaaatgtacctttacaatgaagagatctagcagtcactacct ttaatggttattgaacatcagtagtgggagttgataatccgacatttgtgtacctcatga aaagtaatgagataagaaatacacaacactacctatgtgttatttttgccaaaggtattt aatactgcctctaatcgtaagtaaacagacaaatccagaatgtgggatataatatgaaac aactaaccagactctttaaaaaaaaaaaaaagtcaacataatgaaaaggaagtaacaaca aataaggcagagtgaatgttttaaaatgttaaggagaccaaaaaaagcatgatcaaatgc agtccctgaatcttgattgcatcctggatagaaaaagtgagctttgaaagtcactttggg _. gcctggcatggtggcccatgcctgtaatcccagcgctttgggaggctgaggcagacagat ca~ctgaggtcagtagtttgagaccagcctggccaacgtggcaaaaccccatetttacta aaaatacaaaaattagccgggtgtggtggtgtgtacctgcaatcccagctactcgggtgg cegaggcaggagaattgcttaaacccaggaggcggaggttgcagtgggctgagattgcac cactggactccagcctgggtgatggagtgagactgtgtctcaaaaaagaaagtcactttg agaccagttagggaagtttgtatatgaattgtatactggttgatattgaattaatgttga ttttctaagacatggtaaatggtattgtggttaggtagaattgggtggcgggggggtgcg gaatatccttaatctcagacaatggatacttgggtattaaagggtatttaagtgccatga tgtctgcattttacttccaagtaattcagaaaaaaaaaagtattttttttgtagtgatga aagtaaatatgacaaaacatgaataattggtaaatctcggtgaaagatgcaggtgtctat tcttttaccttttctgtgggattaaaagatgttcaaaataaaaagttggaggaaaatttt taaaaagaaaagcagtagtaggccgggcgcgttggctcacgcctgtaatcccagcactat gggaggccgaggcgggcggatcatctgaggtcgggagttcaaggccagcctgaccaacat ggagaaaccctgtctetactaagaatacaaaattagctgagcatggtggtgcatctctgt aatctcagctacttgggaggctgaggcaggagaatcacttgaacccgggaggtggaggtt gcagtgagctgagactgtgccaccgcactccagcctgggtgacagagcaagactccatct caccaaaaaaaaaaaaaaaaaaaaggacaagcagtaggcagtagtagtcaaatatttata ctctgtggtctttatttttctttggtcccttgatgaatctattttattttttgacgttca ggtttttatcagtatttttttttcttgcagtgagtatcatgaaaaaattacagacttaat tataaaatgatttttactcaaacttgctcttttttctttttttaactattactctgtctt cagAATCCATCTACCGTAGAGGTGCACGCCGCTGGAGAAAGCTTTATTGTGCCAATGGCC
ACACTTTCCAAGCCAAGCGTTTCAACAGGgtaaacatagtttgttgaatgtcgataatgt gaaacagctattttttccctttctactatgaaagaaaggtagtttgttattaagtcttgt tatacacttttaaatacataagtagcatgaccttacatttccagtttgcctgaggcagta tgcctataatttttaatagcatctctttcactcttaaaaatgctccaggccaggtgtggt ggctcaggcctataatcccagcacattgggaggccaaggctgccggatcagttgaggcca ggagttcataccagcctggccaacatggcaaaaccttatctctattaaaaatacaaaaat tagccaggtgcagtcacatgcacctgtagtcccagctactcgggaggctgaggcaggaga atcacttgagtctgggaggcagaggttgcagtgagccgagattgtgccactgcactccag cctgggcaatggagcaagactcagtttcaaaaaaaaaaaaaaaaagctccagattggatg attaattattccacataatataccctagctgtaagaaaattgaattttaaaatataattt aaggcaaccagaaaacaagcaaggtttatttatttaatattaatctttatttttccagtt agtgttgtaatttgattttcactgtttagaaaataataatagcaaacacttatctgggtt gtactacgtaccaggcacttttccaaatgccttatatacattgattcatttcatecttac aacaaccctgtaagataggtactatatgtttccactttatagatggcaaaactcaagtgc agggcagtaacttgcccaagataatacagctagtaagtgatagaaccaaagtttgaaagc agcagtctgtcttcagaagtcagttattcatttattatttatttattttttttttatttt aaagacagagtcccgctctatcgcccaggctggagtgcaatggcacagtctcagctcact gcaacctgcatctcttgggttcaagcgattcttgtgcctcagcctectgagtacetggga ccacaggcatcagccaacaggcctggctattttttgtatttttagtagagatggagttat accttgttggccaagctggtctcaaactcctgacctegegtgatccgtccgcctcggcct cccaaagtgctgggattacaggcttgagccaccatgcctggecagaaacgaattttttaa atactcttgataaccgcaaatttttggatgccatttccattctaaaactaatgecatgta attaattaatgtaaatagaaaccaccacecgaaatccctctccaaactctcttacttcca gtagcactgacatttaagaaggctttgaggctgggtgcaatggcacatgcctgtaatccc agcagtttgggaggctgcgaagggggaacactgaagcccaggagtttgagaccagccagg gtaacgtagtgtgagateccatctctacaaaaaatacaatcattagcagggcatggtggc acacacctgtagtcctagctactcaggaagcttgagcccaggacgttgaggctgcagtga atcaaagtgactccactggactccagcctggctgacagagcaagaccctgtctcttaaaa ataaataaataaataaaaagagagaccaagtgcggtggctcacacgtgtaatcccagcac tttgggaggctgaggtgggtggatcacctgaggtccaggagtttgagaccagcctgacca acatggtgaaaccccatctctactaaaaatacaaaacttagccaggtatggtggcgcata cctgtaatcccagctactctggaggctgaggcaggagaatcacttgaacccgggaggcgg aggttgcggtaagctgagattgtgccattgcattccagcctgggcaacaagagtgaaact ctgtctcaaaaaaaaaaaagaaagaaaagaagaagaaggcggctttgaaatgagaagtca ctttaggttattgctctttaagaaaacagagctttgttttgacctetgaacagcctgcaa ggtttatgtttgcttaggagtccttcaatggctttttctgccatatatatttctagttta attctgttttcattattttgaacttgattatgtaaagactgaaaattcttagacttagaa agaaatgtggttgcagatttcactgtctctttaaaataagctctgtttttcgctgacctt catagcttttaaaaaattatgtatgaggaagctttgttttgcttttgtttttgtttttgt _ gtgggctgacagttgacaccgtgacaaagggaat.tgagtcagcaaactatttgggaaat _ _.
ggttatgaccttcttggttaataaaatattgttgaattactcttttcagCGTGCTCACTG
TGCCATCTGCACAGACCGAATATGGGGACTTGGACGCCAAGGATATAAGTGCATCAACTG
CAAACTCTTGGTTCATAAGAAGTGCCATAAACTCGTCACAATTGAATGTGGGCGGCATTC
TTTGCCACAGgtaagatgtctgtccttttttttttttttttttttaagagcgtgcttgat aacactgctataacagagtgctaaaatagggaggtgttcaggaattacagcacaacagag tagctacagagtat5gggaggaataccttacgttactgttaacacaccgtgaactttgga acttcgaaatatctgtggtaatacttgtctgtgggacacagttaacttctttacctgetg taaaatcctctggtctaaattaggaagctatagagagaaccatttaagagtttttteccc ctctcctttaatctgaacgtattagtttatagctcacattattctagcttetatcctaag cagatatcaggtaagaagagtcaaaggtatcatgtttgttatttaaactgtgagattact ggcgaggaaagcatttaaaatttttatttattaatttctattttaaatatataaaacatg tttgttatcgaaaaaaatacagaatacagatgaataaagaaaactaagtaaaagtccaca tatattctaccatgtaaaggtaattgtcatttggtggatatccttccagaacttttcctg tgcaaatttatatgcataaacatttttaattttccatatggaaaaaatgtaaacatgtat aagagtaggtggaacactataatgaactcccatttactagacatccagctccaacagtta tcaactcatgtctaatcttggtttcatctgtacccccattcacttaacttccccttgccc tgtattattttcaaacaaatctcagacatatttcagtatgtacctctaaaagagaaggac ttttttaaaaacctaactaaaaaacaaattetttatgtcaaatatccagtaagtgttctc ataaatattataattttgtttttatagttttcattatgaatcaggatccaaatgaaatgc acttgtacaattgattgatctcttagatattctttaatttactggttctttcttcatttc tctctcttctttttttccttacaatttaattgtaaaagaaacagttatttgtcatttaca ctgttgtaaaattttgctcattacttctccatggttatgttcagtatgttattgtcttct ttattcttttatcttgtacagtagttggatgtcgaggtttgattagattctggggttggt ttgtttgttttggtggattgtttttgagtcgactttacagagggttgtttatccaccaga aggcacatgtgcttgcctgtgtcttttttgttattgttttgagacagagcctcgctctgt cttccaggctggaatgtagtggcacaatcttggctcactgcaacctccacctcccaggtt caagtgattctcctgcctcagcctcccaagtagctgggattacaggtgtgtgccaccatg cccagctaatttttgtattttcagtagagatggggtttttgccacgttggccaggctggt cttgaattcctgacctcaggtgatccacctgcctcggtctcccaaagtgctggaattaca ggcgtgagccactgcacttggccaatcttagtgaactttctggcaaatcttacttcctta aggatccagaattagaattactgggttaaaagatacgcatttaaaaaaatacctggatgc agctatctaagcacactgcctatcgattagccctgctccacaaggaacagtcaaaaaaag aaagaaaaatacctggatgcatctttctaaattgtcctttagaattgttattccatgttt attcatgggacttgctttggacattgtgaaagcaggttattaccggtagctctttggtat tagaatctttaattagttcatataagcttaggaatgggtttgtagtaaaggggaaaatcc aatcttaaggaaaaacagaaggctgactatttccaacatatttatgtaggttactattaa tatttttgagtattctttggtgacatatggaaggaaagggggcagggttagtgattatat tgaagttttaaaaatccttaagcttacttatgagcctttctttaacgcagccttgaaatg etaactgtatcattaatgttctttctcaagtttactttttcctgetggtattcattaaat gtgagtctaagaataaatcagtaataacttgggtttgaatttacctttttcctgagatta ttcgccattatttgggtaagttggattctagaaagtatttcttttctcttttttggggcc actgacacccttgagaatcttcaggaaaatgggaaacccacaaaattttacatgtaattt taagaggttatagacatcctgaagtctaceccggaccccagctaaagaatgcatattcca gaaacttatttttgecaaagatctgaagtggagcttgaaggaagaataggtagtgttgaa gagaagcaaagcagaatatatggcagtttaatatgatttctaattggtggtctgaaatta gttttgtattttcttttctgtaaaatgtgactaacattacctcattcacagcagtattgt atagtttcataaaacaaaattaaaagtaaattctcacttaagttatattctttcaaaatt aaattttaatatgctgtgtgttgttgaaatagtgttatttctggtgtaatagaggtactc cactgagttactgtgtctttggaaatgtttgtagGAACCAGTGATGCCCATGGATCAGTC
ATCCATGCATTCTGACCATGCACAGACAGgtaagagtggtgctggcacaacccattgttc attcacagagtagcatgtaaagacttacttaggtgactctcttacccaagtttaaaaaca tttacttcttcccaGttaaaagtaaatacatatattttgtagtggtgaaatcagtcacac tatttaacatacacatttggcatttttaaaagacaactgtgggctgggtgcggtggttca cacctgtaatcccagcactttgggaggctgaggcaggtggatcacctgaggtcaggagtt cgagaccagcctggccaacgtggtaaaaccccgtctctactaaaaatacaaaaattagca gggtgtggtggcacactcctgtagtcccagcttctcaggaggctgaggcgggaaaatcgc ttgaacccagaagttggaggttgcagtgagccaagatcatgccactgcactctagcctgg gtgacagaacaagactccatctcaaaaaagagagagagaaaaaaaaaagacaactgtggg ctgggtgtggtggctcacggctgtaatctcatcactttgggaggtcgaggcagaaggatc ----- ccttgagctcaggagttcaagaccagcctggccaacacagggagactc gtctctattta --aaaaaaaaaaaagtatgtaaactacaacaaatgactattttttctagttcacataaattt cttttgagacgcctttaaattcagcaaactcagtttttttecataatgaaaaacatgagg ctgattttgtggcccatgttgactgtgttcaggtgactcgcttttttctttttctttcga gacagagtcttgctctgttgcccaagctggaatgcagtggcgtgatctcggctcactgca tcctccacctcccaggttcaagtgattctcetgcctcagcctcctgagcatctgggatta caggttcatgccaccatgcccagctaatttttttgtatttttagtagagatggggtttca ccatgttggccaagctggtctcgaattcctgacctcaagtaatccacccgccttggcctc ccaaagtgctgggattacaggcatgagccatggcacccagctgaagtgacttgtttttat taaaagctttattatcagaagtagaaattatgtgaaacatagagagatgcaatataggaa attccaggaagatggtgtaactgaaaacgttagatagatacaaaaccttaaacacgtatc tgggaaatttggagagcagtgcaaggaggtagaacagcatgatcttctctggactaaatc aagaaagggaaaacaagggagtttttctggaaagacaaaatgcaatctcgtagtcataga atgatcaactctatgaaatgcaggctcttttttttttgccccaagtagetttaagaagta gaagttccatccttgtctgttctttacttgaccattgtggtagttaggaaaattctgagt acaatggagtgagaagtgaaaaccagaggtcctgtatctctatgtcttagtcatactaaa aaatttaaacatatcatatagagtcatttgtttagaaggaagtgtttgattaatttgtaa agaagagaaatgttttaaaaataacgaaagtacttgttaaaagcagtacttggctaccag gttgtgatgcttgetctctttaccctcactaaagattaggatttaactattgtatttaca tacaatttgttattagtaggacagatagtcagttttaaataatgaaaatttattcagaag taaaaactaaaataaaaatcaggagacaatttttatttcaaactcattaatggttgctgt ttttttctcctgcaccttttttttttttttttttaatgtttggtattgggtttttagTAA
TTCCATATAATCCTTCAAGTCATGAGAGTTTGGATCAAGTTGGTGAAGAAAAAGAGgtaa gataatttgtcttattgtacattatatcattagctttttaataaggctcaggagtttaaa agtatgacatattgacctgcttagactttagatcataatggtgaaatgcaaaaatgattt gtaatgattccagagttttattctgatttaatttagtaattaaattactaatttaaacta ggaaataatttagtgggataacttattttcattttaaaatagcttaatctgaaaattaca atgtatttaaggatactgtttaaaatacttggtagtattgtttaaaatatatagtagacc cttccgttttgtgcctgaattgettatttagacaataaatgattaaacatattaactgtc attgtttttttgactattaagtattttatcagtttttaaaacaaaacaaataattaaaat gatttgattaaaataataatcagttttttgaaaaaagcttatagtgaaaaagataatcat gtctcccaccttecactcccagtttggettcttggeaaccttttaaaccatttctagtta tgtccataatatttatatttctgtttttcaattttttatttttgtgtatttctggacatg aaagatttagttcacactgcctcctctctttcccgtatcattcttttttttttttttttt gagttggggtcttgctgtgttgcccaggctggagtgcagtggtgtgattatggctcactg caaccttaaactcctgggctcaagttatcttcccaccttagcctcccgagtagctaggac tatagccctgtgccaccacacccagctaattttttcattttctattttgtagagacagag tctcactatgttgcccaagctagtcccgaactcctggcctcaagcagttctcccaaatca gcctctctaagtgttaggattacaggcatgagccaccatgeccagccaaaactttgaaac ataaataaaagtaaacaataatataacaaagcccttgtatctattgttagttaaaacagc tatcaattcatgtctagccttattttgtctactcacttccctcactcctgtattattttg aagaaacctgttagtcacctatttgatgttatgttttagtttcttgttctgtttgtctga aaaagtctttttttctttttaacttttttttttctttttattttttttgtgagacaggat tattgcacaggcacccgtgcagtggtgcaatgatggetcactacagcctcaacttcttga gttcaagccacctcagcctctcaggtagctgggactacaggcatgtgtcaccactggacc ctcatcacaatatacaaaaatttactcaaggtggaataaagatttaaatgtaatacctca aactataaaaatectagaagaaaacctaggaaatatcctctcgacattggccccggcaaa gaatttttggctaagtctccgaaaacaattgcaacaaagccaaaaattgacaagtgggac ctaattaaactacagagcttccacgcagcaaaagaatccaccaataaacagacaacctaa agaatgggagaaaatagtcacaaactatacatccaacaaagatctcatatecagaattta taaggaacttaacagcaaaaaacaaccccattaaaaaatgagcaaagggctgggcatggt ggcttacaccagtaatcccagcactttgggaggcagagtcaggcagatcacttgaggcca ggagtttgagatcagcctggctgacatagtgaaaccccatgtctactaaaaatacaaaaa aaaaaaaaaaattagggcgtggtggcacacacctataatactagctacttaagaggttga ggcacgaaaatcattggaactggggaggcggagattacaatgagccaagatcatgccact gcactccagcctgggcgacagagcaagacactgtttaaaaaaagaaaaaaaaaagggcaa aggacatgaacagacatatctcaaaataagacctataagcagccaacacacatgaaaaac cactcatcgtcactaattatcagagaaatagaaatcaaaaccacagtgagataccatctc acaccagtcagaatagctgttactaaaaaatcaacttgggcgtgatggctcacacatgta atcccagcactttgagaggctaaggcggaaggattgagcctgagagttcaagagcagcct ___.., aggcaacatagtctetactaaaaatacaaaaaattagccaggctcggtggcaggcgcetg_.__ tagteccagctgctcgggaggctgaggcaggagaatggtgtgaacccaggaggcggagct tgcagtgagcagaga.ctgtaccagtgcactccagcctgggcgaaagagcgagactccgtc tcaaaaaaaaaaaaaaaagaaaattacaaataacacttttactgtttctctagaagatgc agtgaccttggcacaccttaaattcattccttttccattcctgcetttgggtgttattat tatcagagtttaaaattctgtgtgtgtgtatatttgtttttttaaacagttactccttat gtagatttacccacattttaccctttttgtttttctttccttcctacgtctgttcctcca tctgagatcatgcattttctccttcaagaactcaatttagtttttcctttagtgagcacc tagtagtgatggatccactcagtttttctttgtctgaaaatgtttttetttcactttcac tttgtgagctacttttgcaggatagagaattctaggtcagctgttttcttcttttttagg ccctttgaagatgacatttcactgttaagtggcgtctatcatttcattcagccttattat tgtgtcggtgaagttaactctatcttttttgctccacttgattctctcttatagtttcca gttagccatatttcaagtctatgtgttgacttactttcttacacttctcttctttcttaa ccttctcaaacctggtttcttttcactctgctgtatttacccttgtgtgttagtctgttt tgtgttgttacaaaggaatacctgaaggttgggtgtggcagetcacacctataatcctag gactttagaccgggaggatcatttgaggccagtagttcaggaccagcettggcaacatag caagaccctccatgtctacaaaaaataaataaaaattagccgggtttggaggcacatgcc tgtagccccagctacttgggagactgaggcaggaggatcacttgagcccaggagttcatg gctgcagtgagctatgttcgtgccactgcactgcagcctgggtgacagaacaagacettt tcttaaataaataaataaatgaaggaaggaataaaggaatacctaaggctgggtaattta tacaagatttatttggtgcacggttctgcaggctgatcagtaagtattgcactagcatct gcttctcaggaagctttcagtcttggcagaaggcaaaggggaagcaggtgtgccacatgg caagagagggagcaagggagtcaggggaggtgccacactctgaactcactcattacacag gaacacaccaagccattcatgaggaatctgtccctgtgacccaaacacctcccactaggg atcacattteagcatgagatttgagatttggaggggtcagatatacaaactatcaccttg ttaccaaatcaaattattattattattactattattgacagggtctcactttgtgatgca ggctggagcgcactngcacaatcacagctcactgcaaccttgacctgcctggctcaggtg atcctcccacctcagcctcccaggtagctgggactacagtgcacaccaccaacatccggc taatttttgtatattttggtagagatgaggtttcttggcacattgcccaggctggtcttg aactcctgggctcaatcagtccacctgcttcagcctecctaagtgctgaaaatacaggca tgagccactgtgcgcagcctaaattattatttctaagtttttaagttgtcattctcactc agtttttctaatacccttctttcagttttgtgcttgegggtttctttatctttctcaaaa tttactatttgcttttcttggtattcttcacttcagagatttcatactttattctcatgg gtccattgtgtgctgatgattttgcaggcatctaataaaagactgtettcaggcttctct gtaaattgctagaagcttacatttgtagttgtgaatgaattttaaggcttactttgtcgt cccaaaggggtcttggtattctgtggaaaagaatgtcttccattcgctgaactacttcat gcttgttttctgtctatagcatccaaaaacgcetctgaatgtgtgctetcactagcttac attctatgtatcaagcttccagcagactctttcatcttgatgtctcattataacttctga atttatcatgaaaaacccaatcgttctctccagtaactttgtcaatcttatectagccac acacttgacgttccctgtcagtggtacccecaatctcttggtcaccaaggttaatgtgtt tttttaattcctgcatctctattgcctctgtacccaaaagttatcgtatcctttttaaga catccttcgatgtttttgtgatttcaactccctccccattcttattaccatccctcttat ctcaaaattcatccatataatctggatagttagattatttggtttggaatgacatttgaa aaatattaagaacttaaaatatttttatgttaggaaaatatctttaaatcgttataggta caactaggtgttagaaatataatgtactacgcaaagcatttcccattataactctgatac aaatgttctcaacagGCAATGAACACCAGGGAAAGTGGCAAAGCTTCATCCAGTCTAGGT
CTTCAGGATTTTGATTTGCTCCGGGTAATAGGAAGAGGAAGTTATGCCAAAGTACTGTTG
GTTCGATTAAAP~AACAGATCGTATTTATGCAATGAAAGTTGTGAAAAAAGAGCTTGTT
AATGATGATGAGgtaagcactgcatattttattgcttctaaactgcttgagaatactatt cttttttttttttgaaacggagtttcgctcttgtcacccagcctggagtgctagtggtgc aatcttggctcactgcaacctctgcctcccaggttcaagtgattctcctgcctcagcctc ccaagtagctgggattacaggcatgcaccactatgcccagctaatttttgtatttttagt agagatggggtttcaccatgttggccaggctgctcttgaactcctgacctcaagtgatcc acecgcctcagcctcccaaagttgctaggaatataggcgtgagccaccgcacccagccaa gagtactattttaaagaaaacctctatgtttgtgctttattatctcattctgcttttcta aatatgtgctaagtaaatgaaatatattatttcggtttacttttcttatagatggtataa gatatttaaagtaatttgattattagatttttttaaaaaaacaaaaatcaaaccacatta ttatcaggagaaatacttgagctttgtaaaagttttctagacagttttataatactgaaa gattgactagtgttatttttctctttgtatgtaaattttcgtttcatgattatcaatggt tttgatatttagcctagttaaccattgcatttgtgaccattgaattgctcagagcaaatt -.-_ tatcattaattgtgatatcagtttgacatagatttcttacatgtttcaaaatagGATATT
GATTGGGTACAGACAGAGAAGCATGTGTTTGAGCAGGCATCCAATCATCCTTTCCTTGTT
GGGCTGCATTCTTGCTTTCAGACAGAAAGCAGgtaagattgaaagatagtagaatgatta ctgggcttcatatttttggtcatattacacagttagaacctttetgccctaattcatgaa gttgatatcatggaggatgcaacagtgttaggcttataacttcctgctaataatactgcc atcagtgatatcagtttgatattagatcagcattaggaaatgacctactttaggcagaac aggaaatagccatgtcgtaattatggcagtagaaatccaaccttttaaatatccccagta ttctagttttatgacttaaaattttctagcatttaacaaggaggaaaaataccttgacag tcgaaaatgacttatttagcaaatgctaaaattaggatggtaatgagtggctctggattg caagtggtactactttagaacagaagtagtaggttacaaaattattatcatgctggttta ctttctcgtatgttccgtaccctagataccctttgtttccaccaaaattttggcatcttt ttaaaggctaaatagtagagaatgctctctgttgtgatggtttctgaaaatgcaaagtta cactaccttattttggatcttgatttcatgggttctctcctgtgttttagATTGTTCTTT
GTTATAGAGTATGTAAATGGAGGAGACCTAATGTTTCATATGCAGCGACAAAGAAAACTT
CCTGAAGAACATGCCAGgtgagtttttgtttactgtttgtgttgttttctttttggggcc atgtggctttttatgtgcagtggttggaaacagtagataaataatttattttgatactag ttaattatttgtaagtcatgcagaggctgagctaaaagttaatttacattatatatatgt aaaacaattatatattcttttacatttatacacatacatgtacatacacatgcacacagt gcttcctaagcaattgaaaagtgtgaacagtattaaaaggcaaacctttagtctgctaaa accaatccttttcaaatattatgtctatgtagcatcagccatttaaataattgagactaa taaacacttattagtcttttcaggtttgtagtggtctctcagagagttcttcacgataag agtgctattcatacatacttgagagtaattaaacgatccctctggctgggcacagtggct cacacctctaatcecagcactttgggaggctgaggcgggcggatcacctgaggtcaggag tttgagaccagcctggccaacatggtgaaaccctgtctctactaaaaatacaaaaatttg ctggtcgtggtggcgggtgcctgtaatcccagctactcaggaggctgaggcaggagaatt gtctgaacccggaaggcggaggttgcagtgagcccagatcgcaccactgcactccagcct ggccaacagagcaagactctgtctcaaaaaaaaaaaaaaaagatccctcttaaactagta tatacttctgactgttcttcctgtgatttattgttctttggcttttttttcctctaatcc cataattattgatgaataaaataatatcgaataggccaggcgcagtggctcatgcctgta atcccagcactttgggaggccgaggcgggtggatcatgaggtcaagaaatcgagaccatc ctggccaacatggtgaaaccccatctctactaaaaatataaaaattagccgggcgtggtg gcgggcacctgtggtcccaactacttgggaggctgaattaggagaatcgcttgagcccgg gaggcggaggttgcagtgagctgagattgcgccactgcactccagcctgggtgaaagagc gagactccgtctcaaaaaaaaaaaaaaaagtattgaatattaattttgtgcccttaattt gatattaatatacaagactgtaaattgtttatgtgttggatggaggagataggtgggaag ggatcatggccttgagtaaaaagtttaatccatcagtaccatgttttgtttcttatccgt aatcagcagtaattctcaccctttcctacttcacaagagtaatgccaaaatgaagcatgt gagtttgtatatgtatgttattatcatgcagggaataaatattagaaatttcatttaaat taaaaacttgtagaaaatttgctacttcattattgcttgtcaaaaatttcataagaagat ataaattgtacttgtctaatcttgaggccaacctgggttttttgtttatttgggtttttt tgttgttgttttggtgttcatttatgttcattgtgtatttatgccttatcaaatggtcac ccttcatagagccacagatgatattttgaattgtgaacatagccaatatttgttccttgt ttgttcagttgaatgtgggaaagctagtctggtttttactatattaatgtgccagttttg gttttataccatctttgcttttgtaagaactaaagcccaggacaagggcttaagttccca aatcacggaattaagtagctaggaggtgtatgttacgtacctccacacatgatcatgata atgtgccaccaaagcagccatacatcagctcaggcattccattttcattattcaggccaa aagttctgggttgtcaccagtgagttggtagcagtttttttaagttcttcatttaatatt aaattttacagttgtttatagttgtagaatattttcatttaattecttttctaaaacctt catgaggattttatagtattgagtagtcagettgtagtattctttctattctcgacccca ttagtggttcttagccttctcggaggatcacgggtcccttagagaagtgatgaaagcttt gaggactetgtagatactgtgcatgtacatacgggcatacacctttgcccccagttgtag aagtatggactgcctgaagttcacccaaggacccagattgagaacccctgtttgagacta tcaaattaatagctttatgaaaaatgtgagtttaagttagacaggaacttttacaattgt gtcttgggctcagatgttttaaagtggtacttcagttcatttttcaaatttgttcctaaa atcactgggagaaaaaaatatgttttaatatgaatttttgtgtttccagttgtaaatgta gaacttaaatatggttgaatcaaatgacttattttttatttaattttagATTTTACTCTG
CAGAAATCAGTCTAGCATTAAATTATCTTCATGAGCGAGGGATAATTTATAGAGATTTGA
AACTGGACAATGTATTACTGGACTCTGAAGGCCACATTAAACTCACTGACTACGGCATGT
GTAAGgtgaggaaaGttttctagttattttaaaaggtcttcagcagctagtagtctttgt aaaataacttcatgtttaaagatgaggaaatgattactaattttgctaatttacttaagc ... ...._ tttgtggaattctagcacaaagacaaatgtactttttttctaaccatttgcaaaatt-tgt atcttctgtgttatgtgtactacaataagagctaatttctttttattatacataactttt tatcttgaaagttgaaatacaattgaagacaatttggaaataaaaattgtctgcaattcc actactt~.acacaaccatttgcatatgaccttecaatttttgccatttagtagtgaatct tatataatgcattcaggattttcctcagaagtcaaacattttttatatttaaattttaaa catctgacataaagcataataggataaaacaagaatttcagttactcccggaatatgtct tcatttctttttttttttttttttttgagacagggtcttgctetgtcccccaggctggag tgcagtggcgcaatctcggctcagtgccagctccgcctcccgggttgacgccattctcct gcctcagcctcccgagtagctgggactacaggcgcctgccaccacgcccagetaagtttt tgtatttttagaagagacggggtttcaccatgttagccaggatgatctcaatctcctgat ctcatgatccgcetgcctcagcctcccaaagtgctgggattacaggcgtgagccatcgcg cctggcctatttcttgatgttttattcttttataacagtgttccattttaaatgtctgat attttcccactaaatgtgtaaggaactattccttgttaaggtaactggtacaaaattatc ctcacatagcaatacaacaaccagtatgtaaatgtgtgaattgcattccctgttcacctg tgggaagtgcctccagagectggagattatctaaatgctaacaacatggcatatgacaac ctagttgtatcgaagatttaactttattatctgttcagcatgcattaaagaataaaatct tcacttaaactatgtttgcttttatgtacagaattcaacegtacttttcacatgatactt attaattaattattgttgttttttttttttggagacagagtctcgctctgtcgtccaggc tggagtgcaatggcacaatcttggctcactgcaacctccgcctcctggattcaagccgtt ctccagcctcagccttccaagtagctgagattaaggtgegccccaccatccctggctaat tttaattttttttttttttttttaatttttgagacagagttttgctcttattgcccaggc tggagtacaatggcacaatctcggctcactgcaacctccacctcccaggttcaagcaatt ctcctgectcagcctcctgagtagctgggattacaggcacctgccaccatgcccggctaa tttttttgtatttttagtagagacggggtttcaccatgttggccaggctggtcgcgaact ectgacctcaggtgatccacccgcctcagcctcccaaagtgctgggattacagatgtgag ccaccatgcccggcccttacgtatttatattatacaagttttcaatcataaacaattaga aagcttagcgagtggaacccctatgtacctatcacttatatttgtggtacctttttgatc tctgtgtcattttttttcctaagggatttttttctcatttcagaaaaaagtgacagtgat agaggagtcttatccccaagaataaatgaaactgaacaaaaaacatggagagtattaccc ttcatacgaagtgcacaaattaaaacaatgaggcttttttttttttttttttttttgcct gtgagatacgggttttaaagttagaatagcctgtatgtacaagagtttaaagaaatgggc atatgtcactggtgtgtatataaattgttacaaaccttttgagaagcagtttgatggggg aattatcaggaatcctaaagatggccatgttctttgatccggtaattctgcccttggata ttctgagtaaatattttggtttatgaggagagatttctgaccaaaacttttattgtagtt tatgatcaatattataaagtcatttaagaagatctttatttttattttatttttactttc ttttttttttttttaaatagagacgaggtctcgctgtgttgcccaggctcgtctcaaacc caagagttcataatgttagcatttagataatctccaggctctggaggcactttcctcagg tgaatggggaatgcagttcatacatttacatatttgtcatgttactatgtgaggataatt ttgttccagttaacaaggaaagcaagccaccacgcccgactgaagatatttgtaaaaaat acataacacatgatggctcagacctgtaatcccagcaatttgggaggccgaggcaggcag attgctggagctcagaagttcgacaccagcctgggcaacatggcaaaactccatctctac aaaaaataggaaaattacactgggttggttgtgcttgtagtcccagctacttgggaggct gagatggggggatcacttgagcctggggctgtagtgagctgtaatcgcgccactgcactc cagtctgggtgacagagtgagatcctatetaaaatatatatatatatagagagagagaga gtaataaatatatatatgtatatacataatgcttataacagatgaagtcttaacatatag aattgtctgattcttttatgtatcattctgttatgtagcatcacacgttgattctgttta cttttcagcatttttcaagttgttattttaaaatgttatgttaaatgtggttaccaattg cattacagtacactaatgcattttaataacattttaaaatgttatttttaaataacacct ttaatggaatcactgcattgtttaaacaatcaaaatgggcagggtgtgatggctcacacc tgtaatctcagcactttgggaggcccggcaggcagatcacttgaggteaggagtttgaga.
ccagcetggccaacatggtaaaatcttgtctctactaaaaacaccaaaagattagctggg catggtggcacacctgtggtcccagctactcaggagactaaggcaggagaattgcttgaa cetggaggcagaggttgcagtgagtggagattgtgccactgcactccagtctgggtgaca aagtgagactctgtctcaaaaaaaaaaaaaaaaaaaaaagaaaatcacaaaaatgaatta agacttttctcttggccgggtgcggtggcttgcacctgtaatcccagcattttgggaggc cgaggcaggcggatcacaggtcaggagattgagaccatcctggctaacatggtgaaaccc cgtctctactaaaaatacaaaaaaattagccaggcgtggtggcggacgcctgtagtccca gctactcgggaggctgaggcaggagaatggcgagaacccgggaggcggagcttgcagtga cccgagatcgcgccactgcattccagcctgggcaacagagtgagactacgtctcaaaaaa aaaaaaaggacttttctctttttgtctttcttagtcttttgttactcttactggaaaata atattggcttcttatacattttcatttcttacagggatcctcaatcaagttagtcaaggt gtttcataaatctgagatctttatcgagtaggtctttaaatcaaatgtcctecta-cctcc-ctttctgcctttcctccttctccaagagctgcctagggcgggtgcagtggctcacgccta taattccagcactttgggaggccaaggcaggcggattacttgaggtcaggagtttgagac cagcctggccaacatggtgaaaacccatctctgctaaaaccacaaaaactagccaggtgt ggtggcgagtgcctgtaatcccagctacttgggaggctgaggcagaagaatctcttgaac ctggggtggggtggagattgcagtgagetaagatcacaccactgcactgcactccagact gggcaacagagtgagactccgcctcaaaatatatacatataaaataaaataaaaaataaa gcttatgagaaattaaccctccaaaagtttgaatgctcttttatgacttagtgtcaatat ttaacttacctgaagcttgacttcatgcaagtgttggatgaatttctttataaagattgc agaggatagtgatgaaaacttgaattagtatctttagagttatgtttgaaatattttatg aacgttgattttattaagtggcagcctttcgtggttttatgaactgatgtgcctttaagt gtttttttcatcaacagaggaattctaataatatctgttatgctgcagaaaacttagcaa atggacctacattctgacattcagtcaacaagtgaatgattaagcatagctgttacaagt taacagactacatctcttacctctgactattgtactgaaagtacatgtcatttttcatga gaatgtattgccgttgccaataatagaaaacaataaaaaccatattcatatttctaaaaa tagcatataatatcccttttagaaatcattttaaaattcttggagtcacaacatattact aaatatttcttctagatgtttatagcagtgttatatataacagggtgaaatttgaagaaa aatatgttcaccatgcccagaatgtctctggagggccacataatagtggttgcctctagg gagctggaactgggtgagtcagggacaagaatggaaggaagggccgggcacagtgctcac gcctgtaatcgcagcactttgggaggctaaggtgagtgaatcacctgaggtcaggagttt gagaccaacctggccaacatggcaaaaccccatctctactaaaaatacaaaaagccagag gctcggcacagtggctcactcctgtaateccagcactttgggaggccgaggcgggtggat cacttgaggtcaggagttcgagaccaacctgaccaacatggtgaaaccccgtcactacta aaaataaaaaattaggtgggcgtggtggtgcatatctgtaatcccagctacttgggaggc tgaggcaggagaatcgcttgaacctgggaggcagaggttgcagtgagccgagatcgcacc attgcactccagcctgggtaacgagcgaaactccatcttaaaagaagaaaaaaaagccag gcgtggttgcatgcacctgtaatcccagctacttgggaggctgaggcgtgagaatcactt gaacctgggagacagaggttgcaatgagccaagatcacgccactgaactccagcctggat gacagagcgaaactcggtctcaaaaaaaaaaaaaaggaaggcttgagttttgtgctgcec ctcttttttggtttagaattttgtaccgtataatctataggaaagtggttaagttctagg tacatatgttctgttgaatttcatatagttgttaatattagaaagtcttcggttgtgtag gaaatgcttacaaagttttaaaacatgcttaattatgtatgattcagttgtctttagact tttttattgttgattttttttttatttgccttttggecagagaatggtttgaatattagt tcattggaatacattgagatttcctttatgacctaatatatggccagtagcccatgtgta cttaaaaggatatataatctttacatgcagggagtctctctctctaatgtctctettcct tctccctcactccacacacacatatagacgtacatatattctacatgtatatgtattttg tatatatatatatatattttaactctagcttttttccaaatctttctctgcctactgatt tttagtatgtgtgatctatcattttctaatatagattattctcatattaacttctcctat tatgattggagattgtgaaattctcctaataattttgtccttttttactctttgtatttt gaggccatgttgttgagtgtatgcaagtgtatatttgttacaatttcttggtgattgtcc cattaattattgggtagttcctttactctgcctgttagtgtgttttgccttatttttttt ccatcctacagctattaaaatacaggcccggcatggtggcttatgcctgtaatcccagca etttgggaggecgaggtgggcagatcatctggtcaggagtttgagaccagcctgagcaac atggagaaaccccattttctactaaaaatacaaaattagttgggtgtggtggcacacgcc tataatctcagctactctggaggctgaggcaggagaattgcttgaatccgggaggcggag gttgcagtgagctgacattgtgccattgcactccagcctgggcaacaaagtgaaactctg tetccaaaaaaaaaaaagtgttcttaggaaaaataaacagaaggaaaatattgtagtctt atcaatggttgtattaggaggtgagatttaaagtgcttcttttcttcatgaaatatgcct tattctactaatattaaaattttgttattaaattttaacttgtatgtaaattattttaaa ttcaagtcgtaccttaattgaatcaactctagcaacatctaatgaggacaggttttcttc aagctatttagtggtgatctgtgattttaataataaaggcagttgccaggcatgatggct catgcctgtaatcccagcactttgggaggccgaggcaggtggatcacttgaggccaggag atcgagaccagcctagccaacatggtgaaaccctgtctctactaaaaatacaaaaattag ctgggtgtgttggtgcatgcctgtaattccagctactcaggaggctgagacacaagaatt gcttgaacccaggaggtggaggttgtagtgagctgagatcgtgccactgcatgccagcct gggcgacagagcaagaccctgtcaaaaataataataataataaaggcaattgttctagtg atgttaagtgagcttaatgtatcactgcagatgctgaacttatatgataggtgaaataga aagggtgaatttaaaacagaactttttatctcattctttctttctgttctttttaataaa agGAAGGATTACGGCCAGGAGATACAACCAGCACTTTCTGTGGTACTCCTAATTACATTG
CTCCTGAAATTTTAAGAGGAGAAGATTATGgtaataaataaattggtggtattattttag.-_..-..
ctattgctagatgggtggtaaaatgtggtaccaattgcattacagtacactaatgcattt tgacgtgatcttattaatataaggattcttgatcctgttaaaaactacatggagagtccc agactttgaaatcgagacagtgggaccttggcagtatttgggggtaccaagctgaataat attttattagtggcaaacactaaacagtagcaggcactattctaagcagtttacatatat taactaagttaatcctcttaacaaccctgtgaggtaagtactattaattctccttttaca gttgaagaaactgacatacggaaagtttaaataactcgcctaaggtcaaggattcagaac agcacccatgtgactccagagtcatgaacccctggaaaatttttcagatttcctgggata tttgccccaggaatctgaaagatggtggaaagattaactgtatctcaggcacccgaagat acacttatcttgagaaaacatttgactttttgggttttggccctctgccttcagcagata taaaggacaatgtggtacttgtgagagctgctcaaagtctgaatccactgtccttcactg gtctttatcagctagcaaaagatcaagtttaagaccaaggaggcaggagaatggcgtgaa cccgggaggcggagcttgcagtgaaccgagattgtgccactgcactccagcctgggcgac agagtgaaactctgtctcaaaaaaaaaaaaaaagcccctgtccacacctccagcagttgc caacatatagccgggcgcggtggctcacacctgtaatcecagcactttgggaggccgagg caggcggatcacgaggtcaggaaatcgagaccattctggctaacatggtgaaaccetgtc tetactgaaaacacaaaaaattagccgggcgtgttcacaggtgcctgtagtctcagctac tcgggaggccgaggcaggagaatggcgtgaacccgggaggtggagcttgcagtgagccga gattgcaccactgcactccagcctgggcgacagagtgagaccccatctcaaaaaaaaaaa aaaaaagaccaaggagattactctgaaatacaatttaattatatcctcaacacacaatat tagatattgggcatgagtctgaaagtagaaatacatggagaaagaaagtttttttttetc ataattttatttttaaaattatcttttaggtacctacccttgttgataaatgaagcattt ctataatcttcagtgcctaccatgatagttggaatgcatttagagtttactttttcattg tttctttttcctttatgtgataaaatttccagttactaactttcaagaatgcaaagtgta taatttattgctttaaaatttctttetgaagGTTTCAGTGTTGACTGGTGGGCTCTTGGA
GTGCTCATGTTTGAGATGATGGCAGGAAGGTCTCCATTTGATATTGTTGGGAGCTCCGAT
AACCCTGACCAGAACACAGAGGATTATCTCTTCCAAGgtaatttggagtattttacagag attctctgagaaaaacctattctagagtacaaatgagagtgattcaggttactactttga gtaagaaaaatgagcataatctggaaaatataatcctgactggtggtattaggttttgtt gttgtttttgtttgtttttgagacaaggtctcactcttttgcccaggctggagtgcaggg gcgcaatctcggctccatgcaacctccacctccctggttcaagcaattcttctgcctcag cctcccgagtaactgggattacaggcacactcccgagtaactgggattacaggcacacac cactatgcccggctaaattttgtatttttagtagagacagggtctcaccatgttggccag gctggtcttgaactcctgacttcaagtgatctgcccacctcagcctccccagcatgctga gattacaggcatgagccactgcacctggcetctgtgtattaggttttgatgttttttaat acattetttcttttctatagtcttcactcctgttcacagttaccttctcatactcaaaat cataacaggggttatttagaattatccatcacaaacagattggagaaaggaatectgtgg ctagagagataatctttacacagggaccctgaggctgagtgcataagttcaagaacagta tgaggggaaaatagagcaccaagatgatgagtgatcaaaagatggggaaaaaaggcccca catcagggaatatacagaattgacagaaacaagcagacaagtgcagggacctctagcaca gaatccaaagaagtatgaaaactactataaaattctacatttaataattaaagccatcac aggatataaataggcatttcatgcccaaatggccatggaatatgtgaaaagacattcagt ctcactagcaattaagggaatgcacattaaatgttaatgagttaccatttcatatcggta catttgatcaaaatattaaagttgggtaataccagtgetggtgaggatgtggagcaactg gaactcttctagactgctggtaggaatgaaaactgacacaacagctttaaagaataattt ggcagtgtccaaaaaaattgcatattatatatgctaagcattttacaaatgttaactcat ttaaacctcataacaatcctatgaagtatttttttattcctattttacagatgaggaaac tgaggcataattaggtagtcaaagaataagacattcatgtaaatgataaatagtattcag attagaggctttctctgagaagatgggaaaagaaggggtttaggaaagtacaggaggcac ttcagttatatatgtaatatcttattttttttcctggaatgccttaaatatcttataata aaaatttaaagattgcacccaggcatagtggctcacatctgtaatcccagcactttggga ggccgagatgggcggatcacttgaggttaggagtttgagaccagcetggccaacatggca aaaccccgtctctactaaaaataaaaaaaaattagctgggcgtcgtggcgggcacctgta atcctaactactcaggaggctcaggcaggagaatcacttcagcctggaggcggaggttgc agtgagctgagatcgtgccactgcactecagtctgggcaagacagtgacactctgtctca aaaaaaaaagaaaaaagaaatttaaagattgccaggtgcagtggttcacacctgtaatcc cagcactttgggagtccaaggcaggaggattgcttgaacccaggagttcaagaccagctt gagcaatatggtgagacccttatctctacaaaaaaatttaaaattagccagccattgctg ggcgcagtggctcacacctgtaatcccagcactttgggaggctgaggtgggcggatcact taccttcatgaggtcaggagtttgagaccagcecggccagcatggtgaaaccccatctct accaaaaacacaaaactcactgggcatagtggcacacgcctgtaatcccagctactcagg .__ _. _..
aggctgaagtggtagaagcacttgaacccgggaggcagaggttgcagtgagctgagatcg tgccactgtgctccagcctggatgacaaaacaagactccatctcaaaaaaaaaaaaaaaa aaaatttagccgagcgtgatggtggcgcctgtggtcccagctacttgggaggttgaggtg gaaggattgcttaagcccgggaggtcaaagctgcagtgagctgtgattgcatcactgcac tccaacctgggcaacagaacaagcccctttcaaaaaagaagaaaaaagattaaagccatg taaaagttaaatataatactataatttttatctttctagTTATTTTGGAAAAACAAATTC
GCATACCACGTTCTCTGTCTGTAAAAGCTGCAAGTGTTCTGAAGAGTTTTCTTAATAAGg tataaattgtgtataagaatattttgtgatttgtctctttctatatatatcaaactggtc agtagcggtttgggaaatgtaaaattccaaaacagtagagaatgtaactttttcagtttg acccagaatttgtctcttacccaaagagtaattgacagcattagatcctgagataagtta gttgtcctttccattttggcaataaaatttactccccagctatatattacataatttttg tgtatgtgtaaataatatataccatattctcacataggggaagagttaatctttgggttt agecataattgtactttgaactctgtttccattttctctgtatcattatccatagaatct atttattaccatgtactttttgagcacgtgggcegcagtgctecctacaaattctcatgt caaaaatgctataattaggtaagattcggaagaaatgaaatgctatctttggctcttaaa aatgtgaacatcattcaattgtttgttgctgttggtaggctagaggagttttaggatcta ggagtgtggtcttggcaattataaattctactttaaataaatggtatgatagaaaagttg atgtacatttaccttctaaggtaaatagataagataatgagttttaataaaataagaaat tgaagccttttaaaaaatgaacaatttatgtgaggaaagatttaaacttgaaacctaatt tttcacatagtgaaaaatgaaggcaagaggtgttgatatgcaaaataaaataccttttat cagaaagaaaaatgggaacatattctcattcatagtgatgaataagccaagactttttat aagttgcaggctcctcagtccagtgattcagataatggttgtatcattgtcttacacagg tggtggtttgttgctataattgggcatggggattttaaattaagctaaaaacaaacttct catgaagtttggaggtttgcatgttttgaetctcacactaggtcatgcaaagaaatggct gggtgctgtcaaatgattctgctgttctctttttcctcctgtttttctttagcaaggaat tggtgatgattctctgttttaattacatgatgggtggagaaagtgccttgaggaatcaca agtttcaaataactcaatttgttctggagttgtactttctagaaataaaaggtagaccat tccaacttcagaaataagagtatcatgtgagggcacacaacacagatcacaaagatgatt tattttaaagcatgacattcacccaattcttgaaacatttctttcaccatagGACCCTAA
GGAACGATTGGGTTGTCATCCTCAAACAGGATTTGCTGATATTCAGGGACACCCGTTCTT
CCGAAATGTTGATTGGGATATGgtatgtaaattttgattactcaactattaggtttcatt attatcttgggccaattttttgttgttgttctgtttgtttttagacagagtcttgctctg tcaccgaggctggagtacaatggcacgatctcagctcactgcaacctccgcctcgcgagt tcaagcagttctgtctctgcctccetagtagctggaattacagtcactcaccaccatgcc cagctaatttttgtatttttagtagagatggggggggtttcacaatgtcggccaggctgg tctcgaactcctgacctcaggtgatacacccacctcggcctcccaaagtgctgggattac agatgtgagecaccacacccggcctatctcgggccaaattttattgtcttagctaacata tcacagctttaaaaacttaaaaccactttctaaactgctttttagaaaacttttaaaaca aaaaaaaaattcaatttttttttaatttattattttttttctgagacggagtctcattct gtcacccaggctggagtgcagtagtgtgatctctgetcactgcaacctccacctcctggg ttcaagcaattctgcctcagcttcetgagtagctgggattacaggcacacgccaccacgc ccagctaatttttgtatttttagtagagacggggtttcatcatgttggccaggctggtct tgaactcttgacctcaagtgatccacccgcctcagcctcccaaagtgctgggattecagg ggtgagccaccatgcccagccaaaaaattgaatattaatgtaataaagcaggttgtaatg ttattaaggcccatatcaatgtttatacttgtttttatttttttaggagaaacagtctca gtccgttgcccaggctgtagtgtagctcacgacagccttgattgaactcctgagcttaag agatcctcctgtgtaacctcccaagtagctgggactacaggcataagccatggtacccag ctaattttcaattttttttttttttttttttgagatggtgtcttgctctgtctcccaggc tggagtgtagtggc~.caatctcagctcactgcaaccttcgccacctgggttcaagcgatt tctcctgtctcagcctccagagtagctgggattacaggtgtgtgccaccacacctggcta atttcggtatttttagtagagacggggtttagctatgttggccaggctggtcttgaatcc ctgacctcaggtgatctgcgcaccttggcctcccaaagtgatgggattacaggegtgagc cactgcacccagccaatttttaatttttttatagagatgggatcttgctatgttgtctgg gctggtcttgaactcctggcetcaagtgatcctcccatctcaacetaccaagcggttggg attacaggcgtgagccgccatgcccagctcatatttgtaaattatgttcatcattgctaa tatcattgaaccatgcttcaggactcactttaataaggtaaacaatgagtgcagaggaga actgtagaggtggagtttttctaagaatacagacttgagctgtcatccagtatgtctttt cagATGGAGCAAAAACAGGTGGTACCTCCCTTTAAACCAAATATTTCTGGGGAATTTGGT
TTGGACAACTTTGATTCTCAGTTTACTAATGAACCTGTCCAGCTCACTCCAGATGACGAg __ .. _ __ taagtaattctgtacactgaaatttttttttaagttctttggaaatcccatttttagtga . _ .
ctatgcaatgtttcattatcagattatactataatttttttattttetattttatttcat tttattttattttgagatggagtctcgetctgttgcccaggctggagtgcagtggtgcaa tctcggctcactgcaacctctgcctcccaggttcaaatgattctcctgcctcagataccc tgagtagctggtactacaggcgcgtgcegccacgcccagctaatttttgtatttttagta aggacagagtttgccatgttggccaggctgatcttgaactccagacctcaggtgatccac ccaccttggcctcttaaagtgctgggattacaggcgtgagccactgtgcccggcctatac tataatttatacaaccattcagttactggtatttgtatctactgtaccattataagtttt aatagtaactgtcattttctcctttgctttatagtgcattatcttattttcacaacaact ttgtaatctagttactgtcatcttcgttttacagatgaggaaaccaaggctcagagaggt taagcaaagttacacagctatcaggtggcagagtcaggattcaaacccaaatctgactga ctaaggcctgtgctctttctaccacgctgcactgtttcccatttgacaaggactgtcttt gagttcctgagtattgccttaagatagattcctagaaagagaattaggtcagagggtatt aacattttaaagctrttgtattgccaaattgctttttttaagaaattacattgagttatt aaatccagccatcagtgatetggtatattttttgtgcttatacttcatcttttaaacatg tagtttggaataattgggagatattttgattatttacctgttgttacagattcattctct ctaatctcagggaggcccttattgtttggcagtcatttcacttctatctcatttcttacc acatttctcccagcacctgctccaaacagtctcttcatttcagaagccttcagttctact cctttttccatcactgttaatggattaaccttgtcttaatttgatgcaaggactgataac ctctctgacgtgaccttgcctcctttgcagctgtccccagaccaccttgcatctcagaat tgctttctaactcttttcatcattttettattccctactcttggaagactctcctttaca aggggtgtccctgctattttcctagacctgtttccttagttttctccaagatttcatttt gtcagttatctttttattagaccttctttatttttttctagcttgtttccctctgtgtaa gr_atgetcagatactctgatttttccccctaactcatggcccctctttgaacaaccacgt ttttcctcattttcatttcatcttaaagcctcaaaaaaaaaaaagttaatagatgttcat ggtcaaagaaaaataaatacacagcacctctaatcaaacttcttcagactagtcaacatt gattgtcttgaattttttttttttttttttttactgtcaacacttcaaccccttacaatc gaacctgtcctccagcttttgaaggttgaatcaatttcttaatttctaaattgtaaagca ttttggggtcagtcctcctctcccttgattaatgtaaagcatttggtactcatggctttg ccttgggtagcactgcetattctggttctgtttcatctctgtgactactttcctctcatg tgttttccctgtccccttgagaccaggatgctccatggttctgttcatgacagccttctt tttgctatatgcagtttgtaccttggagatttcagccagccctgtagcatagataccagc taattaaatggctctcagttaaatggcaaatggttattgagcaaaaggtgttatggtaaa tactagacattcaaagacaatcaagacagtctgatctccccaaaagcgtgetgtctacta gaggagaaagatgtgtaccaagtcattatttctgacagcattgtgtattagaaggaacac tggatttaatcaaaagataggagtttgaatcccgatgccacctcttaccaactgggtaac cttggataggaattgcataacttctctgagcctgttctcaaattgcctacctcataaggt ~l tgctgtgaagaataaatg~catgatggtttctgaagcacttatcccctgcegttagatctc ctgagctgcatttetgtttaacacggcccccagtttgtcagccaagcagctcaaatatat gaagtctaaaatgaaagtaatgaccctttatgatctctttctattgttctcaatcagttc ctttttttttagttacctaattetgctcacggtgtgtccctgttgttcagattccagatg tcagtgattgtggactcctectttttcttaacagattacataatacctgcagctgccaag tctttgtctgtgttttcattatttcatcatttacatcagatctttcttttctcttcccgt tgacacaccctagttcaggcctcattcaagtcatacecagagtattgtatcagcctccta attgatctttactccttcactttgcaacctattctgtatgccttgtgaagtaccactcca attcttgaacccctttaattagaaaccttcagtaactccttcattgcctatcaggtaaca tctatcctcttggctagcatttaaggcctceccacatctgctccagcctgactttctagc gatacctctcaccataatacaaacagtgttctgatcagtcttagctactcaccattccct agtagtattattgtctctgcttctgcctgttcattcctgtgtatcccgccttcattttta cctattgaaattttcccatctttcagagccacctcagatgcaaccagatctttgatggat caaggtgaaactccttagtgtaaacatcactggcctctttgatttagccattatttttct tcagcatcatctaacacacttctattcctgtgetccaccctaattacttgcatttcccaa gacctaccacagtctttcatcattccattcattaagtgtttgcagaatgaatactgectt ccttgatttctccaactagaagtcacacctttctttagaaccatggttagaacaggactt agcttattgtgtataaaatttaacaagtactgctttctcttccagtaggaattacctccc ttccttgaaggaagggactgtatcctctgtaactttgtgcttcttagtatggcataatac atttatgtattaaatatttgatagcactactcactgtatattaaagtagaagcccagtgt aacaaaatgccaacctctcccctctctgtgacccatgatctccctgcggtgttctctcct cattccaggtctctcagtgtacttgttcctattgccttttcettttggctaacttcttct gggctacactatctaacatctggetgttgaggtgactactaaattgaatgctaattcaaa ___., _, _. cctggatgttcacctgtaactaggaatgttgttctggtcaaaagttaagattaactggaa _ ._"
tggtgacaactggtgtcttttttattcgcagtcctcagttttgaactectttttggctct aaacttgcttgtgggattatcggggttttttaaattttcagtactccattcttgattcgt ctagaaaatctgggggattaatctaaaaatttatagatttcctttcagtacaattagcct aattacttgatttttaatcttattttaccatttaaaggttgaagaaatcttgattatgat gaaaataaatttatttttctttcaacagTGACATTGTGAGGAAGATTGATCAGTCTGAAT
TTGAAGGTTTTGAGTATATCAATCCTCTTTTGATGTCTGCAGAAGAATGTGTCTGATCCT
CATTTTTCAACCATGTATTCTACTCATGTTGCCATTTAATGCATGGATAAACTTGCTGCA
AGCCTGGATACAATTAACCATTTTATATTTGCCACCTACAAAAAAACACCCAATATCTTC
TCTTGTAGACTATATGAATCAATTATTACATCTGTTTTACTATGAA1~1AAAAAATTAATAC
TACTAGCTTCCAGACAATCATGTCAAAATTTAGTTGAACTGGTTTTTCAGTTTTTAAAAG
GCCTACAGATGAGTAATGAAGTTATCTTTTTTGTTTaaaaaaaaaaaa SEQ ID NO: 7 Genomic sequence for PKC zeta I/PKC zeta II (protein kinase M
zeta) gene from human. PKC zeta I and PKC zeta II are alternative transcripts from the same gene.
(exons for PKC zeta in capital letters and single nucleotide polymorphisms are indicated in bold) >chr1:1939456-2130465 ATGCCCAGCAGGACCGGCCCCAAGATGGAAGGGAGCGGCGGCCGCGTCCGCCTCAAGGCG
CATTACGGGGGgtgagcggcggagagggcggggageggcgcgggtgaggcagggagggcg gggagggctcagecgtcggggetcctgegcgagagggagagagggaaggggcggcgaggt cgctgcgggcccggggctgtcgcgggaggtcctcggtccccgcccgtgagcgtcacccgc ggacacgtcgtggacagcgcgggctccttceccgggaccgggtttccctggggtcggccc cgcgccgcgagctcctcggcccggtcattgtggtagacgttttcgctggaaagttgggcg gggacgttccggccgcaaacctgtaaggactgaaagttttcatcaagttgtgaaaactcc tggcgggtttcttaaaatcagcgtttcctaaacgttctccacgtttacccggtcgggggt ctcgctttagccaaaatccggagacccggggcgcgggcgctgtggctccaatgcagcccc cggcagggctcggggeggtcgggcggggacaggggtttctggaggagacggtggggccga gactgaccctggggtttgcgtcgcacccgccceccggaggcccttgcctggctgtgggag ggggcgcggtcaggtgctggagcggaggggtcctggactcttggccgccgcctcggggca gcgctgctgggggtggcgggggctgcaccaggtggccgggctcacaggcacagcggaggg gtcgctgccccecgaagtgtgggcggtggggaggggaggacccgtgggtttgttcttcca cctgtgcgcgtctccaggagccccgaactgggacctccgctcccgcgagggtggctgctg ctgcagagagggaggggagcagaatgcgggctceggacttgcactggctggtccttggga tctcgaaaagctgetcctgccccggtgegtcctcagctacagcgtgggcaacctgagccc cagaggcagggacggccggcagggttaggcgggtgacatcttccccgggccatgtcctct caggacagtgccccgggggtctctatggtgccctgcgagtctgagcgggttcagettctt gcgaaccttgtctt5;gggtctcgggtcagccatctggggctgcttggcccegggtttgtt gaggaggctcaattgtctcttctttgggaaggttggggcctctgcagctcccctgtggca agcacctggaaccttcggggtgcagtggcccgggtttggtgccagaaccagaagaaaggg atttctgggggactgaccgtccagccctacctgaagaggtagggcagccatgtcttttgg cctggaggtcagcaggttaaaacttggtatggttgacgttctggctattggacttgtcca gggacctgggcttcctgtctccttgccattctggagccaccacactgggcaacaggtgat ggtgcggagctcaggggagtcctgcgagagggaggtccacacccgaggggctgcaggggc ccagaccctcctgcattccggcgtccaattcctgggaccaaggctcggaggcaatgccac tggagttctgggccgccccgtcctccctctgccttgctttggcccctgggagcactttgg tggtggggcgggtgtaattccacccggtgactctggtttcccaggctggagagaccaggc tCCCaCCCCttCCtCttCCCtCCCttCCCggaCtC'tC'tCCCCtCtCtCCCCa.CCCCttCC
tcttCCtCCCtCCttCCCtgttgttttCCCtCCtCttCCCgCtCtCCCCtCtCtCCCttC
CCtgCCaC3CCtCttCCttCaCCttCCtCCCCCttCtagggCaCgtCtCCCCtCtggCtC
ttCCCtgCtCCtaCCattCCttCtCtCCtCtCtCCCCtcccaggtCCtCCtCCtCtCtgC
tgcagagtgtgaagtacccttctccccgttctggctcctcgtccctctgggcacccggtg cctctctgaggggactggctgtggggtgggacactcaggccttagggcaatgacacagtt ccagaaagcggctgccaggatgagtactgggttattgaaagccctagaaactctgtccct_.._.
ggggtgagacgctgctgtccgtgggggtagctgagcgtggacacgtggaagactagtctt tagaaaaaggaagagcacttcagtcacceccatggggcatggccaccccgtcatccttgc ctgtcctcccagggccctctgagcacacttgagatccaatcctcgccaccccaccccgcc ccctgtgggcctgaggggtccccaggcacctgtgttttcagggagtcccaggtggcctgg gccagactcccacgctgagtctcagatgcccgctcttctagggccacaaacactggtgct ggctcttccctctttcagctcagacttttttttttttttgagtctcgctgtgttgcccag gctgcagtggtgtggtctcggcccactgtatccttcacctccgaggttcaagcaattctc ctgcttcagcctccctagtatctaggactacagacgcccgccaccacgcccggttaactt ttgtagttttagtagagatgaggtttcactttgttggccaggctggtctcgaacttctga cctcgtgatccgccegcettggcctcccaaagcgctgggatgaaaggcgtgagtcaccgc gcctggcccagctcagacaacgtttgtgttcagggagcttetgtgtgcaaagcccagggc ttggtgctgaggccaacagagacgcaggagtctctcccgggcggcccagctggctgctgg gtgctgagtcctggacgcccctgctgaagggcacagggcagctgtttgattcaggattgg gatagggttggaggtggtggcctgacacttcccaagccctggggttttactggagccacc cacctggcctctagattggccggaaactggcttccactggaggcaggactgtaggggtag gggcgtggggcaggaagaggtcaaaggtgaagtgatggccgactcccactctggagttce tggtggtcagacttttggactccaggtcaggcagcaggcgtggatgtcagcttggggcga ccccagggtgatgggtgtgtgacccccctccattccttactttcctaatctgccatgatg ctgtgggctgtggcgaagaccagccaggttggttcctgtggggtgcttgggcactggggg caggtgctgggtggccagttccagcaggaaggggtgggtagctggggcgtctgtccccca ggcccaggtggcccagggtgactgggtgaggcctgtggggcaggtgggccctgggctgct gtgtcagggccgcggctgtggaccgatcctgtgttctgtttgcactggagttcttgtctg ggatgagaactttgtttcttgaaacttgtctgatgaattcagataaccttgatggggagc cagcagtgtcagcgaagagcagagcctgtatctctggttgggacatctcacaccccttca ggcttctttttataggccctgtgctcttgccccgcgctcttgtgggtgtcagaaagccgt agatttttctgaaaattcagtgtgttcacaagggtgtgattcccgctctgagtttcagga aacaccagctgggccctgtggtggtccctcccctccacgcagggtgagaccagctcttgc tcagtgcaggaggtgaggggggacctcgggtccctatcagcagggaagtgccagccttca aagggtgcctgggagtccgtgagcttccccagcccctggagttcaggtcctgtctggggc tgaaaagataaaacacactgactctgtgtgactcggttttaaaaaaaaaaaaatctgccg gggcttctgccgtggctgcagcaacggacccagtgcccactccggggtctaaagagtggc ctttcattatggaattatttaatccccgccacttcaccgctggcaccgtcgaggtctggg ggcaggtctgactggtttcctttaccttagtgaagccggcggcctgcaccgacceggctc gcgcccatcccggggtcacccacatttgggtgaacttgaacgagtgcccgaccaggtaac gttgccggacctcccacaagagggcactttettttctcecattttgtcctcattetttcc agccaggtaggtcgcgcttttttctctgtgcaaggaagttgatggtggtcattttttttt ~3 ttttttttttaatacggagtctctctctgtcgcccaggctggactgcagtggcgcgatct cggctcgctgcaagctccgcctcccgggttcacgccattctcttgcctcagcctcccgag tagctgggactacaggcgcccgccaccgcgcctggctaattttttgtatttttagtagag acggggtttcaccgtgttagccaggatggtctcgatctcctgacctcgtgatccacccgc ctcggcctcccaaagtgctgggatgacaggtgtcaggcactgtgcttggcaatggtggcc attttttaaactatggttatggttaatggttctattttgtgtgtgggaggggggaggggg tggggctgtcatattgtctttggggaaagtttcatttatctaatcaatgatttggttagt tggtaatcattttttaatttgattcaaatatgccccacggtaacagatgcccatgtcccc tctgccccagGGACATCTTCATCACCAGCGTGGACGCCGCCACGACCTTCGAGGAGCTCT
GTGAGGAAGTGAGAGACATGTGTCGTCTGCACCAGCAGCACCCGCTCACCCTCAAGTGGG
TGGACAGCGAAGgtagcccttgtcccatgttggccagaatcctcagectcaggggacttc gccagggcagcctctgtgtgcggagtgtgctcagccaattctgtggggagacttaaagct gtggaattaaacttgttggcgccaacttttccccagtggggatggtgggaaagaggttgg ccacagatgcttatcaaggacctgggcccagatgcccctaggaagggctctggtcttgaa etgcctgcagggggtctccctgccccaccctgggcaggtcctcacctcttcctctgacct cctttctcatgtcctggcctttttcggtaggtgcttetgaaaggatgggctcttcatatt etagggaccacggggagggcacaagcagccagggcctgccgtgtccacctcctgtctctt agacacatcctgaa~.aacaaggggattgggagacgtccagagagacccetttetcccagg gactggcgggcagctcttggccaaggacacggccgtgcgggtggagcctgatagcgcccc cgttgggttgggtacagccctgcagggectgggttctgtacacctccatgtccctttcca gccatagagggcaaggagctctccctecgcccaggactgacctccggagagtgtcctcag ccccgctcactgcttagccctccaagtggtgcccagggctgcaggtgtactgacttccct tccggggtggctctgacgctgcaccgggggccaggtgactecctagtgtggacggccgtc __ _ cttggacctcccgaccctgecaggaggtggccagtctgagcatcgggactttgcccccca ._...._ ccagacccttgtctggtgtgctgagcgggctcgtcacagccccctttgcctcgggccttc ggcgacgtcagcaccgtctcctgccccacccagGTGACCCTTGCACGGTGTCCTCCCAGA
TGGAGCTGGAAGAGGCTTTCCGCCTGGCCCGTCAGTGCAGGGATGAAGGCCTCATCATTC
ATGgttagtggcggggtctgtggtgggcagctctggggggctgttcctggctgtgggtgt ctgccgactagctgggggatttaaaatggtttaaaatectatgatgccagagaatttagg gatgtctaatataatgccatttgggtttttttctttgactttttttttttttttttgaga cggagtcttgctctgttgcccaggctggagtgcagtggcacaatctcagctcactgcaag CtCCgCCtCCtgggttcatgccattCtCCtgCCtCagCCtCCCgagtagCtgggactaca ggcgcccgccaccacgcceggctaattttttgtattttttgtagagacggggtttcaceg tgttagccaggatggtetcagtctcctgacctcgtgatctgcctgcctcagcctcccaaa gtgctgggattacagatgtgagccaccgcgcceggccttttctttgacattttattaacc caaatgaaaactgctcttaacaaagaacccgtaaaccactcagaggctccagtggccagc gtagggccegcggcgcatgtggacagaggggacagccccaccagccacctcacctgcccg gtgctccctaggcecggctccaggctcacagctgtcctcagctttaagttcaaagcccca tgatgagctgacgcatgggagatgtgattgtgatcatttccactttgtctttaggtgggc gtgggctcctccccggtactgctgggggtctgcagggcgtctggggcctgggaatgtggt tccagcgctgtggccagccggtcacgtctttgtctctgtgtccacttctggcgtagcttg ggctccttgccaggcgtctggccatggacgattgagtccaagatgggaccaaagctcgaa accacccatggatttctgacagatccatcattctcctggacaccgggctacctggttaca acacttaattttcttcgccctttatatcaatgaggctctaaatttaaagactaggccggg tgcggtggctcacaactgtaatcccagcactttgggaggtcaaggtgggaggatcgcttc agcctaggagttcaagaccaacctgggcaacatagtgagacceccccctetccaaaactt gttttatttttttgagacagagtctggctctgtecccaggctggagtgcagtggcactat ctctgttcactgcaacctccacctcccagatataagcgattgtcctgcctcagcctcecg agtagctgggactacaggcatgtgccaccacacttggctaatttttttttttttttagtt ggagtctcgctctgtcgcccaggctggagtgcagtgacgcgatctcagctcaatgcaacc tccgcctcccgggttcaagcaattcttctgcctcaccctcccaagtagctgggactacag gcatgtgtcatcacgcctggctaatgttttgtatttttagtagagacggagtttcaccat gttagccaagatggtctcgatctectgacctcgtgatccacccgcctcagcctcccaaag tgctgggattacaggcgtgagccacggtgcccggcctaatttttgtatttttagtagaga tggggtctcgccatgttggccaggctgttctcaaactcctgaccttaggtgatctgcetg cctcagcttcctgaagtgttgggattacaggcgtgagccacggtgcccggccccaatttt tttttttttttttttttgatattcagacgtggtggtgcacctgtagtcccagttactcgg gaggctgaggtgggaggattccttgagcacaggaggtagaggctacagtgaactgtgatt attccactgcactctagcctgagtgatggggcgaaaccctgtgtcagataaataaattca tagatgtgcctaatctagtcctttttattgtggttgtgatagtaagcacattttgcctct ctatgtggaaagatacagtggcttaaaaattcacattgttttctagataaaagaaaaata gggctgggttcagtggcacacacttgtaatcccagcactttgggaggccgaggcaggtgg atcacttgaggtcaggagttcaagaccagcctgaccaacatggtgaaaccccatctctac tataaatacaaaaattagccgggcgtggtggtgtacacttgtaatcccagctacttggga ggctgaggcaggagaactgetggaacccgagaggtggaggttgcagtgagctgagattgt gccactgagetccagcctgggcacagagtgagactccnatctgaaaaaaaccaacaaaaa acaaaaaatgtttgtttttttaaagtttcaatacttttatgtgtatacacacacacataa aaaagtagagatggggtttcgtcatgttggccaggctggtcttgaactcctggcctgaag ccatcctctcatctcggcctcccaaagtgctgggattgcaggcgtgagccatcatgtcca gccaagttttaatactttctaagcacctattttaataatttattgtggaagcccaggata tatgttaaaataattttgaactetgtcttgagtatgaagaagtggaatctaaagtgcttt taaaagtcagtgttcaaagtaattgcatttctttcccatttttatatagtttaaaaatac aaatcagtagcttcctctgatggctttgctgtccaggtccctctgattgccttttactct aagtttttccgtgggttttaaagtcggagcctggcctacgtagatgcacggggttttgcg tctcccaggagcgggctctcattggcagtgccacgtgcgccttgcgtgaagtccacgtgc tcagcctgactgaggcgggacttcctccgtgagactgttgagtggcagccgcagggtctt gacgctgtctctttctctctcttgtccagTTTTCCCGAGCACCCCTGAGCAGCCTGGCCT
GCCATGTCCGGGAGAAGACAgtgagtactggggtttcctacgccggtctcgcatgttacg gggttgaactgttgatccgttgtgccacggaggtggcagtggtgccgttttcggaggttc accctcgtggagcgtcagggcaggagcagccatggtgaccgcgggtggggttttcactgc agctgctgcctgtgcgtgttctggctgacagcaccacatggcgggggactcgcttggctg gttggtagcatgagaagtccaggggtgccctgccgtctccctaggagggaggggccaggt gggaggctggacactgctcctttgtggctgcctcagctcacgaccacccctaggccagtc .... gtctgctcctcctggtccctgctggcccctgagctggtgtgggggctccgttcatcccac __ actggetccattgttgggagaggaaggagagtgagtcccgggggctgtggcttcagaggg aagcttctgacctcacttcctactgcatcccggagactgttgggccctgagcaggtggct aCgCtgCtCtCgggCCgCgCatCCCatggCtgtgcttggtgggggttCCa.CCCCCdCtCt ccagaccccacacggcctccagcatccgtgccatgccttgtttgttgtgtgggcaggagc tcctggaccgaggccgctgcctgtccagcgcagggcacgtggctcagtgcccttcgggca gggcttcccccacccctgctgccagggcacacacetcgctggcctcaggctggatgctgg gtgttggcagtgccctgtgttgggcgggaactgggggtgggagcagattcaggccaagag ggtgagtgggcagttggggcgagagtcttggcttccagtgagaagtggggctgaatagag gtttggcagtgcttagcatagggggcgagagtctcggcttccagcgagaagtggggctga atagaggtttggcagcgcttagcgtaggggaggccccaggagccatgggatttccatgat ctgcccggggagagggcggcgtggcatcccggttccaggccctcagccaaccggggtccc tgcaccgtggccggcaaggccgaggagccatccggaggtgggccctggcaggaatggagc gggtggtctggggctggacctgccggcaggaggagatggggtatgtccgtggcaggcgga caccaccaggtggttttggcagcgcagggcgagtgtgaggaggcagggggcggggaggct ttggaggcaggtggccagacggtgggcgtcagggccctgatcacctacgcagctgccctg gtggtgacctttcccgggaccctccctctgggtgcccacgcctcacggaccctggagcac gcaccctgggagggcacggttcactgcgtttttatagatacataaacacataaataggac agatactccctgtgggtgagacgatggttgtcccctccacagegccctgcagcctcatgc tgctgctttataggaggggacccacgggccgtgtttatttgccacctgggtgattttttg acttggtgacaggactgtgctcctctgtcccatgtgtgctgagactgtgcactcccagag gtatccacatgcggccagtgtagcccctgggcgcgggggaagcccaccgtatttctccga catgtctgcctcttgtctcaaccctgcctgggggcctggggtctgctctttctgtctacg acctcggcattgcctctctgcccgtgtggacaacctgccggccttgcgtagggaagggag gcccgcatttgctcggccactgcagtggaggaaggggaggttggggggtcacaggatgtc cagaggcctgagctctgaaggggagtgtgtcatgggggtggcagccgagtcaccgtgggg aatgcggagaatgtggccaagccccgaggaaggacctcctgggacacgtgagtaggtcct tgagatgtttaccaggggtggctccacggcttcggggaccactcagcctggttggggaca ttccgccagagectctggggcagcetttgccgaggaggtcagaggcgggtgetgggggtg gggagccctgccctgccctgtgtgctgatgtccacccggacgtgggttgggtttcatggc gctagtgtcaggagtgtgtgagaacacactgcccactcggggtcccaggccaccagggct tagggggctggcgctctccctgatgtcctgtgctttctttcactctgactgtggtgctca tctcagacaggacaccctgctctggttgccagtggccgccgectggggctctgtggtttt agegcctgtgggggtgttcacaggtgtttttgacctcaggcagcactgcccaggctgagg gtcagtgagaagggtcggactgggaggtgtgtacagtggatggagcacgccagaggcaga cgagggcaggactgcggctgtaccgtgggcetggttcagacggctggacgtgcctgtctc accgtcagcagaggaccttctggcacattctatgtgtgtctatatgagtgaattggtttt ~5 atagatttttaaaaaaattctaaagtatacttacaactatcatctctatgtagttacaaa cecaaaatatattcaaaaagggaaccccgtgcccgtcatcggtcactccctgttctgccc cagccccacctccgctcagcctctgtctctgtggccctgcggattetggacgtttggtgt ccgtggaatcctgcatgtttgtccttttgcctctagtggctttcacccgcctgacctttc caaggttcatccatgatggggcattcttggcgctgcagatcttttttctattctggtaaa atgcacataacatctatttttgecatcttaacttttttttttttttttttggcagagggg ggacggagttttgttctgtcacccaggctggagtgcatggtacaatcttggcttactact actctgcctetcaggctcaagcggtcctcatgcctcagcctcccgagtagctgggattac aggtgtgtgtcaccacacttggccgagtttttctttttgtagagttggggttttaccatg ttgcccaggctagtctcgaactcctgggctcaagtgacctacecatcttggcctcccaaa gtgctgggattatagatgtgagccaccgagcctgtccccatcttagccattaaaatttaa aggttcaattcactggtattcgatattcgcattgctgtccagtcatcatcacegcccatc tccagaactctcttcatcttcccagactcagcctctgtctccatgaaacactcactcccc attctgcctcccccageccccatcacccacccgccgctttctgtttctgtgactttggtg actctaggggcctcctgtgagtggaatcgcacaggatctgtccttttgtgacagcttatt tcactcagcaccatgtcctcaaggcgcagccatgcgtagectgtgtcacagtctccttcc ttctcaagactgaaccgcaggctgctgtatggatgtattttgtttacccatttctgtcag tggacacacgggtgacttccacagtttagctgtcgtgaatgatgctgctgtgagcacggg tgcacagtgacctctggagaccctgccttcagttctgggtgtagacccggaagtgagatt gctggatcattgatcattctatttttattcatttatttttgagatagcgtctcgctctgt cgcttaggctggagttcagtggcacgatctcggctcactgcagcctccatctcctgggct caagcgattctcctgtctcagcctcccaagtagctgggactaaaggcatgtgccaccacg cccagctaatttttgtactttttgtagagacagggtttcatcatgttgcccagactggtc _. ttgaactcctgggctcaagcagtctgcccacctcggtctcccaaagtgttgggattacag_ gcgtgagccactgcacctggccgataattctgtttaaagagccgccgtgccatttcccat ggtgcctgcagcattttccaccccctgcaatagtgcacgagcgccactgtctccgcatcc tttccagctcttgtcgttttctgttttttgacagtatcttatgggcgtgaggtggcatat cattgtggttttggttctcatttccctggtgataagtgatgttgagcattttttcatgtg cctgttggccatttcttttttttttttttttttgagttggagtcttggtctgttgcccag gttggagtgcagtggcacgatcatggctcactgcaatctccgcctcccagattcaaatga ttctcctgtctcagcetcctgagtagctgggattacaggcacccgccaccatgtccagct agtttttgtatgtttagtagagttgggggtttcaccatcttggccaggttagtcttgaac tcccgacctcaagtgatccacccacctcggcctcccaaaatgctgggattataggcgtga gctgccgtgcccggetttgttggccatttctgtgtcttctttggtgaaatgtcttttcgc gtcctgtgtccatttttgaatgggttgtttggtttttttgttggtgagtgttactagttc tctgtcctggatgttaatcccgtagcagatatatgattagcaaatatcttctcctgcttt gtgggttgtttttttactttgttgatagtgccttttgatggacaaagttttaaaattttc ctgaaatcctgcttaatgtttttttcttttgttgcctgtgtatttggtgtcacatccaag aaatcactgccaaatcgaatgttgtgaagcttttccccttctctttcatctaaggatttt ataattttaggttttatgtttaggtcatggattatcctgagttaatttttgtatgtggtg taaggtaagcatctaacttcattcctttgcatgtggaggtccagttttcttagcaccatt ggtgaaaagactccccattggactgcattggcacccttgttgaaaatcgtttcaccatat atgggagggttcatttgtggagtctcttctagtccattggtctctgtgtctctctttgag ccagtgccacactgttttgatcactgtagctttgtaggaagttttgaaatcaggaagtgt gagccctccagctttgttcttccttttcaagattgttttggggtcctctgagattccaga tgaattttaggacaggcttttctatttctgcaaaaaacattattgtgatttttgcaggga ttgcattggctctgtagatcactttgggtagtgctgacatcttaacagtatgaagacttc caatccatgaactgaagtgtgtttctgtttgtttatgttttctttgatttctttcagcag tgttttacagttttccttgtacaagtctttcacccccttggttaattcctaaacgtttta ttctttttgatgctgttgcaagtggaattgtttccttgatttcccttttgggttgtttat tgtaagtgtataaaagtgcagttgatttttgtgtgttgacttttttgcctgctgttttgc tgaatttatcagttctaacaactttctgtggaaactttagggctttcttacatgtaagat catatcatctgtatacagagataattttactttttccttcctaatttggatgccttgtat ttctttttcttgcctaattgttetggctagaattccactactctgttgaataaaagtggt gtgatcggccgggcgcggtggctcacgcctgtaatcccagcactttgggaggcccaggcg ggtggatcacgaggtcaggagatcgagatcgtcctggttaacacggtgaaaceccgttct ctactaaaaatacaaaaaattatccgggcgtggttgcaggcgcctgtagtcccagctact cgggaggctgagccaggagaatagcctgaacccgggaggcagagcttgcagtgagcggag atcgtgccactgcactcctgcctgggcaacagagccagactctgtctcaaaaaaaaaaaa aaaaaaaaaaaagtggtgtgatcaatcatccctgcctttgtcctgattgtcaaagaaaag ~6 ctttcaggttttcatcactgagtgtgatgtctgctgtgggtttttcatacatggttttta ttatgtcgagatagtttccttctattccaagtttgtcaattgtttttatcaggaaagggc tttgaattttgtcacatgettcttctgcatcagttgagacgatcatgtgttttttttacc ttcattttgttaatgtggtatattactttaattttcattcattgaaccatccttgcatcc catgaaaaaatccttcttgctcttggtgtgtaattttcttgatatgctgccgaattcatt ttactagtattttcttgaggatttttacatccgtgtttataaaggacaattacatctgtg ttaataaaggataattatgtccatgttcttaagactcaatggtcagaggctttcttgtcg tgactttgttgggctttggtgtcagagtagtgctggcctcacaggatgagtgaggaagtg ttccttcctctttaatttttttggaaaagtttgagaaaaactggtgttagttcttcaagt gtttggtagaatttgcctgtgaagacatcagtccctgggetttgctttgttgggaggttc tctttctttctctctctctctgtctgtctctctgatggagagagtgcagtggctcgatct cagctcatgtcaacctctgcctcctgggttcaagtgattctcctgcctcagcctcctgag tagctggcattacaggcacatgccatcacacccagctgatttttgtaattttagtagaga tgtggtttcacatgttggccaggctggtcccgaactcctgacctcagatgatccacccac cttggcttcccaacgtgtagggatttcgggcatgagctgctgcgcccggccctgctctca tctttattattcccatccttctgccagcttttggtttgttctttttctggttccttgaag tgtaaaattcggttgttaatttgagatctttcttgtttttttatttcaaatatttatcac catagccaggcgccatggctcatgcttgtaatctcagtgttttgggaggctgaagaggga ggatcacttgaggccaggagttggagaccagccttgggccacatggcaaaactgtgtttc acacacacaaaaagttcatcactataaattttctccttagcattgctttccctgcatccc tgaaatgttgatatgttgtgtttctgttttcattcatctctcagcatttttctgattttc tttgtggtttcatcttctatccattggttgagtgtgtagtgttatttccatatatttgcg aattcttctgttttctttctgttaactgatttctaagttcatcttgatgtggttggagaa _-.tatactttggataatgtctgttttttgaaatctaccgcggctgagtctgtggctcacttg _-..
tgttctgttctggaaaacgtcccgtgtgcgttgagggtgtgcagccgctgtgggtacagc gctctgctgtgtctgtcagagctatgcgggttactgtgttgttcaagttctctgtttett tacgtgttctccctagttgctttttcattcctttttatggctggatgaattctgtgatgc gattcaccctgtctgtccgttcctctgctgatggacactggtgggggctgggtcgttcgg ggctgagcgtgtgatgagatcaggagcgcctggttttttgggggaggtgagggctggtca cgccccggtcgagtggggatcccctgtgtgcatctgtggcggcctcagtggtgttggggt ggagtaatcgggcggtggagctggggtctgtgggctccacctgctgccacgtgtgccggg ctgcccagggcccatgagggtggtggcacgggggtccgcatgaggggccgcaggtgcctc gggcccctetcccgcttgtttctccatcttcactgtccgttcactgcagtgccgggtgag gccagtgtgtggceggtagattccegggtacctcttetttgeeectccttgctgtatctg gtcacacagaaatggtatgtgtgatttttgtttcaatactcaaatctgttaatattttec cttctggettcccctagtgatacaaatatattttcttccattttggtctttgagctgctt tgcctgtctgtgtctggggtggcatccgctggcacctgggctgacctgggacggggccct tctcttggacttgagcagatgagactcacagcccgaaatgcagcagatccctcaggccac gggactctggacgtgtggcggccctgtcggcctgagccacatctgctgtgagaggcagca gtacgttccttggggcagcagcgagagcaaggctggatccaaagacctccgagcagctcc tccggggcagtccccagctgcaagccacagcccggccctggtaacgggagagcatcgcta gggaggggtggggcggcccggcttcgatgcggccatgtgggagggccactctcagagacc ccccgccttccttgccacecccaccccagaggggaagctggagctgggaggctgcagacc caggccaaggtgtggccagggctggctttcttgggaggctttgagcatcctgcttcctgg ccacccagctctggggctgctgtcaactcttgatttgtagacatcactccagcctctggc ctgtcaccctgaacctcccccatgtctgtgtcttttctcactggaacaccggtggtcggc tttggggcccaccacggcagtccaggacattcaccttgagacctggccttaatcacacgt gcaggaacccttttccaaaggagggtcacgctcacagcttctggagtaggacatggactt gtctttttggaggcccatcctcaacgcaccacagttgactacatcaaggtctgcctctga tctggtgggagtgctgggtggtctgtctccaccagcactttgtgggtgggctctgtcccc aggaaatgctctctgcccaggcccccgccccgtgagaggttcgtgctgccagtggcgctg gtcattgggaccatgtgctgggccggcgcctggcaggacagacagcaggtggctcttctg taggttcttctggctgggacaggcccagccggtgctcagcggaactgagactgacgcccc tttcggacccctctaagaagggaggectgggtgggcagcctcccctcagagttggggaaa cgtggcccagttcccgccagtcaccaccctgccggctgccacggggacacgtggcetggt tcctgctggtcaccaccecgccagccacatcttgaacggcgtccgttctgcagtcgcttg tccttagtgttccagcaacaccccaaccaatgcgacccccggaacctccgtcagccccgc ccgggagagccctcccctgcatccgtgctgtgcttgttgaaactgagatcctctagcctt tggcctctccggacccagccccagctgcaggccccagccatggtggtccctttgggaggc gtggtccaggaggtgatgggcagctggagaacccccgtgagtggaggctgctgtacctgg cagggagggtcctgggcaagggggcatggagtggaaagggagtgggtgtccagaaagttc ctggggctccaccaaccagaacgttgccattaccttgagcaaacgacctgtttagtggtg ccttttctttacctgtaaaacggggtgattgtaaataaaategtgtgtaaaagtgcttag gaccagacccccattggagcgagtgttgatacctgtctcaaaggacagtaggtggacgtg gcagggagggagatgtcaagacgacagccagggccctttctgccacttcccctggtgggt ggtgggcggtcccctgaaccctggcagtaagcgagggacctcccgacaccctggctcctc cgtgttggctccaggggcttcctgtttetagatggccgggcecatcatgtgcagggaggg gtggatgctataggcagcagccccagtettcctttgggtggggttatttctgctgctgct gcagtccagaggetctggggctcctcagtgggtagcctcaggcctgggcagcgtccatgg gacagggtggtccccagtcaggccccattggcctcectgtggtgtgtggtaaagactcag ggtgcccgccctgtggaggaggtgccgggggtagcctggctttgcacccagaccctgctg agggcagcgctggatggtcagctggaccaggcctccgaggtecttagagtccatggagga aatacaaagtccgctgggctgggcagcegcagaceccacttagcagctggtggtgtcctc ggggtcatcagagccagtgctggctgccctgtgcatttcatgttgttggttcctgcctgt ccacagcacagatggcatacccgggcagcgggaccctgctccagcctgcaccctggggaa aggtgtcctacattccacattctgcccgtagcaggcagccccaccccactgtagcccatc ttgtcacttagggtggtcccggtagtggettctggagectggaacgcttgggtcaggccc caggcagctgggaccctcccgagcctcaccccttgggtctggtggggcccctggggtttg gccgggaggacaccgtgactactgcctttgcctctgggtatattccctgctcagcecctg aacccagctccaaggccatttctacttggcaagcgggaggttttcatggccagggatgtt aatagcaggtctctggatgcaagggtggcaaagtcgccttggcctgtgtaggggaagtgg aggaacctgggctctcccgggccggtggtcctggggcagatagcaggggaaggggetgca gccatgtgggtggag~ccatgggggccgtggaggggcccttcctgaccccacagtgggggc ._.- .cagggtggggctggcgggggacagtcctcagctgcaggggctggggtgaggctggcgggg...
gacagtcctcggetgcgggggccggggtgggccaggaaggggaaggggctettgaggctc cggggccttctggctgtagtgtctcacttggagcaatggcgggatceccagatccatccc ctggcccgtctgcctcccgccctcatagccctgtagcctagggcagagaggggtccttgg ccgggacaccatccccacagggacgtggagggtgctgggcccggggctaccatggagtcg cctgctgggagcagccagtacacctgggcgtgcgacctgggcaatgcgggggccgattgc tcaggggggcgcctgcactgccaggttcaaaccccaceggcagggagcctgcgctgtgac ttcaggcatgtgggtggggctccccgtgccccgtgcctcagtttcctcctctgtaaaagg gggctttgtgaggctcgacagggtttagaggagctcctggaacatagtaagtgcttagca aggccgtcttgccgtctetcccacccagggagggtcaagtgggaagagagcggccccacc gagtgtgttccaggccecggcggcgtctgagaggaggcggccaaacctagtggggctgcg cgaccgcctgtggaacagtggggacgctgctggtgtcctccaggcctgggtgggcgggtt accacggaagcctatcaacggatgcctgtgattccctggtatttataggtatgtctattg ttttattaaaaaatccagtttcattcagctttgtctcaaattatttgcaacaaactggaa aagctagttttccccctaaaataggcttctaataaaattggcaatttgcctgctgagect gaatatcctagagttctgcaaagctggatattttgggatggattagaagagaggagttgg ctgaaggacagtggtcgtgctgctgagccggccgtctgtgtgaagtttacactggaccag gataaatgcgtatttcctgtgggagctcagcgtggccatggtattcggtggtcttatgat tttataggcctagccaggggtctgcgagctgcttctgtccagggccaggtagttgaagcc tggggttctgagcaggcgtgggcagcacccaaggaggtgcatggccgtgtcctagtgaaa etttatgcacgctgaaatctgaattttatagactcttccggtgtttcaaaatattatcct tttcattttattcagccaattaaaagcgtagaaatcctagcttgctgatttggagcacta ggcagtgtaggttgccagccctcgttccccatagatttgggaagtcgagtgaaacgcatg tgttaggtttatatgtttcacattttacggaatgcccctcatgcagctggtcagccgcct gacgagggaagcttggccctttggagaagtggccgtgectcgtggtgagctgctgacaga gctggaatttgaacccggggctctggcccggagtccactccgtgaatgcagataaacaca ggtttatgagcttgatgatttaaatggaggttttattactgttcaggcaggtgtgggagg ccagccatcaggagatgatgccgttgagaaggtegtttattactcagcttctgagaggag acctcctcttgcctcgcggggccatgcgggcaagcgccgggtgggttggaggcaggggga tgtgtgggtggggcctttactgtggtttccatgggaaaggtgtggggagcaggcattggg tcggccaggtggagtaacttcagcaggctctggggtgcaggggctgtccctgtgacctgg ggaggcccetggggcgactgggggcccgtgtaggaggtgggcccaggtgagagttctggg ttggtgggtttgcatttgaaaggttcgctgtgggacaagtcctttgctgtetctaggaat cggttggcctctcggggccgtccctccagggtcagcagggccataggtgctggagcatcg agggcacagcacgtatgaatgcagggagcgtgtggtgtgactggtcagagccagaggtct gcaggacactcccctctgtccctctgcacccccagtgcgaagcggcccatgtaggctcag cacgagtgccgagtgcgtttggggaagtgggcagaattcccagetgagcaccccgcgacc ccccatgttttttatgattggaggaaaatgccaggtctcacttgccagtgatgaccaggt cccagggtttgtcagggtaccagggtaggggttggagggtcaggccacccagcggcggtg gcggctctgggtctccctaggagcccgggctggccacagecaggcacagcacagcccgtg aggtctggtcttgggaatgcgggtgtctcctgcettaggctgagggtgtgcgtttccagg ccagccgggacagttttcagcctggggaagcttggcctttcctgttcctgccccccagtg cccaccgtccccacacacactggtggggtttgtggggtggacacaaccacatcgcaaggc ccctatgcctcctctcctcecgctcegttcctgggctgcgggacagtgctcggggccctt ggecattggtgtcgagcccattcacagcctctggacgcaggtcagaggtcactcgccacg gccacagctgcgctgtcccccactcccagcctggcagaccaacctgcaggaccccgggct tagctgggttctgttccgatgtcgcattttcaaggtccgctgagtccgagccctgcctgg gtctggctgctgcccgeccgctctctggactgtgctgatgcagagatgcttgttttcctg tgacgtcagcgtcagctcctgcacatccatgcegtgttttagtttgtgcctcagctgctg gctacagcttcccgggggagccgggtaccacccgggcctggagacatgaggaggcaggga tgtgaggggcgggggacaggacagccggccttccgttaaatatctgctcctcgcgctcga gcctccctgcctattgtcggggccggaggcgagccgacgcagcatcagctcgtcaacggg aaggaagatgcctccctgcacgcccgccgcgcacagagcataaagaatctgcgctgagga ggcaggagaagaaagccggtgagtcgggggcatctcccccgtggattttccgcgcceccg gggccgggccagccgtgctgcaggccctgtgcgtgcggaggacggtgcccgagtcagcat tttgggtctgagtce:cggcgttgccgctgcctgtgcgctgcacagatgetccgggcagca acacggctggtgccacggeccggggaaggcgtgcggctgcagcagctcccagcaatgtca ggggaaacgcagtgagaggctgttgttttgcgggtgacagatttttagaaaaataaggct gtggagggaccttctgagcgaggcaggggctgctggagggacatgctcaccccgaggacg gatggtgtgtggcccaggcctggtggatgegtggcggtggctgtggagggctgggggccg --.--. gggggcttggggaaatcgtcttgggctcgtctgcctgcctggccccagggagttgctggc--tgttgggagtttcactgtggccgatgctttttggttgtgggtctgtgggtctgtgggtct gtcggggccaggacggatggccgcttcgtctccattctgcattgctgcaggtgggcagat tgatgagaccacgggtgaagtctggagaccccaggtgccagggctggtagtggtaacagc cagcacctgttccaggcctgcggtctttccgtctcgagcctgcccteccgcctgtctgag cccccgttttgcattgacagtgttgggttggagtctgggtggcacggccagggttaatgt gcacggctcactccatcggggtcctcggatggtggcgaggagcggggctgcggcgtcctg ttttctattctgaaatggttggaggtagactcggaggggtctgggggctgcatggtgttt ggcagggatgtgggaatgtgggtgcttttctgacgaccattttgcaaggtgtttttttta aaaaaaaaaacaacaaaaaaccaaaacaacaaccagcctccccagtcaggcttgtgggga gccgtgggcctggggagactgggctgctgaaggtggggactgggctgctgggggaggcgg ctttccctctcggggggtgctggctgctggggaggctggcagcgcgcccctcccccaggt gcgaagggacctcagcagacgcagggctgctccgcacagccagcttgggccgcaggggtc cttgagtgatgaagattctgtgttgatggggtgagtgggagagagacggagctggggtgg ttttcacacgtgcgcctgcctgcgaggagaaacgtgctgtgtcatagtttcctcggtgcc tgggacggcttggcctctgctttcgtgtgagcccacgctggccatgcacagctggcacga tccctegcggtgtgaatacactgctggggtgggagcgccgtggccagggtcaggattcga gcggttactggcttttggtctgatggccctcggtgggtgagtcagagctgggatggggac agattggaggggccaccggctgccccccagaagctgtttcgtgttgatgetgccggggcc agctgtggtacctgtgtctgtgtctcggccagatcggcgcacatcttccgcgttcctgtc ccagctgcatcagccatcagtgggggcccttctccgaccgtcttcctagacttcagagcc actggtggttatgtaaggagttgtgtgttectctgcccaactccgagcttggtcccacct cccagactcacctctgggetccgggctctgctgcgatgtttccgaggctcccagttaatc agatctgtcagcccagtgtccacagggtgcctgagageccagcccatccacactgggtgc cccagaccttccacggggtctggtggggacctgccagggctgtcaatggccccagtggag aggcccactgagcatcctgagaagttcctgtgcttgtgacctgctctcgtgtgtgtagca gcgggggctgcgtctcatctgecacacgtttctgatcgccgaggactcagccgggcacat ggaggttgaactgttggggggcgggaggaccatccatggggtcaggcaccaacctetgct gaggatcccaaaatgtggggtagccatcctttcttgtgctggcgtggagcttttcccagg agctgggcagggagctgtcacagggccaggcccctgaatgggctgtttggggccgggget gagggggtgcccagtgccatcgaggggaagectgtgggaaagtgtgatgacatctgaaaa accaggagcaggtcccttgctgtgctggtcgtggtgctcgagtgtgggctcggcaggtct ggtctcctggcgcccactcactccctggccatctccccacctccctcacatggcaggggg aagtggaacgtgcggccactgctcccacegtccctcacagcacaggctggacaggcaccc tgaggcatccccatctcccagcccctggggttggcatgatgctgggcctccagaaatgtt tgtcattttatgcaaagggcagaaaaagctttgttcaggccaggcacagtggctcacgcc tgtattaccagcactttgggaggccgaggtgggggatcacctgaggtcaggagttcaaga ccagcctggccaacatggagaaaccccggctctactaaaaatacaaaaattagctgggcg tggtggtgagegcctgtaatcccagccattcagggggctgaggcaggagaategcttgaa tccgggaggcagaggtcacagtgagtcaagattgcgccaccgcactccagcctgggcaac agagcgagactccatcttgaaaaaaaaaaaaaaaggaaaagctttattcaaaagaagcca cetgaaccagtcggtcgtccagtgttcagcttgtttttggtcataaagtggtggcacttg tcactcatacaggagacgctgtggcagagcccctccacgcatcggggcccggcagctcat ttctaggattctcetgaacacgcgaaggagggcacccaccacgctcgggactggctgctt ctctgtgaggcctccaggcagaaccagtgattccaccgtegtggggcagccttggtgggc ccacaggtctgttgttccccctgagagaggatcagagtcaggagaggcgagacaccaagt tgacacgaacagatccctgctgccggttgttctggtggtgctgtgagcacgtctgacggg tgtgagggtgctggggcttcgtttcgtccacgctcacgtatcgggcacacaggagagttt acacgcgctctggtgggtggaaggggccctgacttgatgttattttgaaatagggggttt gagtgtgtctggtctttctgaagttttcttttttaacgtctcttctgtgggaagtttgaa aagattcaaccgactgcaagacggagccgccctgtgtctgttggggctgtggggacccag gtgcactggcagctcagccgcatcgtgggcccagatggcttcttctgtttgttcctcagc gaaccttgattgttgaaagaatcccgtgaggctgtgtcaagtgtagacaggccaggcctg gtgtcttgtcctggtcaggaaattgtgttgttgcccttgttaaatggttgtgtataaagt ttgcattgtacattatatttaaaattttattttgagttttccatattttctattgtaagg tgttgatagttctgtgggactcacaaagagagaacaggtgtccctggtcctccctgctgc cccagctccactccctggaggggatcacagcagtttctttttgacatttatttccagatt tctaaatgacacatttctgctgctatttctagtcgtttccatttaggatgttacttccct actttctctgggacacatcagctcatctcttccttccttgttccatcctcctgatggagt tatgtcactgtttattgtttttaatcattgagtgtttacctaattgcgggtgacgtgaat _... atgcatgagctaccatgattgcattcccttgttggcacaacttttgggtttccttggagt_.
taatacattgtgattgtttaaatcagtttcctagatgtcttgtbtcaaatttactccagt ttcctcttcccagaagaggggcageteecaccgaagcctgcctcacctecctcctggtgc acctggccccccacacaacatgccgtggggcttccctgtgccccgagctgggaacagtcc cctcctctctcctctgcctacagtcttgatctctggetccctctcttcctctttcttggc ttaatgtccggttaagaccctccagcagetgtctgagaaagatggcgtgggaggccagtt tgggggatctagttggaaaatgcttttcctccagccacacacttaaggatagtttagcta ggtatgaaattctgtattggaaagaattttccctctgcatttcgaagggatcgctctact gtcttctggcttcttgtgtgaccgagaagtcaggtgccattttgattttgtgtgtttttc tectgaaagtcttgtagaatcttttgtcttcagggttctcaagtttcatgataatgttcc ttgtcgtggaaacttctttgtctcttgtgctgggaactcgtgctgtggaaccttgegaca tttggatgtgaggagctttacacccagttatttatcacatggccgactccccgtctctga ctctcttttagagttaacgctgattatttgttggccctcecaggctggtcctttaatttt cttctctattttccatttctttgtttatgttatatgctaggagacatcttcaggtttctc tgtccaaaccatctgttaagtttgttagtttgttgccttgttcccgttcttgtctttcga tcttttttctctgaaggtggcttttttttttttttttgagatggagtcttgctctgtcgc ccaggctggagtgcagtggcgtgatttcggctcactgcaacctccacctcctgggttcag gccattctcctgcctcagcctcctgagtagctgggactacaggcgcccgccaccacgccc agctaattttttgtagttttagtagagacggggtttcaccgtgttagccaggatggtctc gatcttctgaccttgtgatccgcccgcctcggcctcccaaagtgccgggattacaggcgt gagccactgcgcccggcctgaaggtgcetttttaaggcagagtgccctgcccttgtgtca aaggcatatcgcactttttctctggggttattcgtcccggctgagaggcaccgcggtatc atgtggtgattgagcagcacccagcacattcatggctgcgaggcttcccgtgtgtgaact catttaatcttctcagttccttgtgggcaccattgttttctttgttctgggtagagatta gcactgaggcacagacaggtcaagaaatttcccagaatcgcacagtttgagctgggactc aaaccccaagggctgggcttaagcecacgctatttgccgcgtgccccagggcctgaagct gcgtggtcaggccccagctetgctgcccaccagccacgtgacctcggccacaacgctgtc caccgtgtcccggaccctcataagtgagcgtgatggtaaaaggcttggctcccaaggcta tcatgggattagccagtaactaagccacaacgctggccccgcggctgctgctgatggcgg cacatggtgggagcatgtgtgctggcagcggttggtgataacgtctccttttggtgtttt ctttggcctcgtactcagctgttttcaccgagagtccctttttgtgtttgtcctggcctt tgcggcttcctgggcccctggtgacccgcatttgtctgcccacattgactcgtggggcac cacagagctggtggtggcggaagtccccaggggagtgtcctgcctgggagggcegggcgt ctcacccctagtaaggagtctgctgcccccgcaagccctctcgttccctggctgctttgg gtgaggaagggggtctgggggtcgactcctcactgactgggaccctgcacagcaggtgcc ccactttcctgetacctggagcctctgacttggggcccttctttggggttcggcccagta cagtctcctggtggccacggggccetetgcettccaggteccagggcatccactacccgg cctgtectcctctttgctgttacgggttttttggagtttttcttcctttggtcttgggag ggagagtcagtcagtgatgtgtttgagctgctgtgtccacctggaaaccatcgtgatgac gctttetgaaggctaaagtatgcaggaaaaccagagttggagaaggtctttaggtagggg cagtgcgcgtggacgtggcggtgcgcgtggacgtggcggtgcgcgtggacgtggcggtgc gcgtggacgtggcaggtgtggaccagcacgtcccactgctctgcatcctgaggggccgga gggtgtggtgcagggttttaaggagggcaaaggcccctctgtttgtttttccttgatgct gccccccgtgcgacctgggggcagttttcaaatgcttgacccaggtagtttggttctgtc accccctcgttcagtggggtggtgggaagaccagtttttggaacagttttggatttacag aaaaatcaggacaggagtagagcacaagcattcectccctgctccctectggtcagcgta atgcgtgagttacacttcaccagccagtctcggcacctttccagctaaggctttattccg cttgcctcagtctcccctcctgccccctttctgtcccaggatcccgtccagggccccacg tggcacttggccgtcacgtctccttaggtccctctcactgtggcaggtctctcagacttg cctcattttcaacgaccttcgtagttttaaggagggctggtcaggtgttttgtgggacag cccttcgctggggtttgcctcatgtttttctcataaggactggggccttgtgttttggga ggaggtgaagcctccttatatcgctgggtccgggtccacaccctccacgcagcctgtccg tgctggccttgcgtgtcacctggccgcggtgtgtttgtcggctcacacctgcccgtgcct ettcccccgtgctgtcctgtctgcggagtgaggcgtgcgtggcccacacctaagaggtga ggagctacatacgtgatgtcaagttttgcacgggacttgtacgtctgttctcccattggt tatttaattattcctttctgttcatgtggactcgcaggtgtcaatttcatacttgggtta gaatcggataccgtgtcgcttacttattgctcagattgttccagctttgggcactggggc ccctgcaggctggctgttggggcagcgatgaggccagacactgggtgggttgggggtggg tgctgacgggtctctggcaggagggggcaggctgcagggagcagggggaagcaggtccca ggcccagaggtgggtctcgggcgagtctgggctgtgggcatggacccccagaaggggcct gtgtggccaggacgtcccatggctgcagacc.ccggtgtggggtgtgggccctgggaggtg _.
attggtactgcagccggagctccagcatcatgccaaggtggtgctgggtcgaggcgggga ggggagaagtcaccacactgtgeccggacttggtggegtggtgatgtcggggctgcggtt gggggactgaccecgcatactcttctcccagctgagttggcagtgctgtagggtcagcag cccaggctctgcatggggctcgtgtgggactcggcaggtccctgcatcacctggcaccaa gCtCaggCaCgCCCCCCaCaCCCCaCCaCtgCCgCCCCgCCCCCCagCatCCCCttCCtg ctgccctctgtgctgcactgacttcctcagttggtttgatgagaggtgacaaaggcagaa atgggcagagagcggcaccatcgctggcccctcttgcccatttgtcccctgctgggtggg cagtcctcttttttcggaaatgtgttcagttctcttgcattgcataatttgttcatatta aagcaggcttgatccgggctgccgtggttccgatcgactccgaataggacaccacacagt cgtgccaagaaggcgcctaagtgtctttccacacggccatccgagggeggacgtggtcag gggtgctggacgcgtcagacgggttctttgcagcecttggcagegtcgcccgctctgtcc cgcctgttgtgtgcgccttttccctgctccagggctgtgtatttggcaagagggaggctc cgtggcacgatcacacgtgcaggagctgggggctgccagagcggctgttcaagatggact tggcaaatcacctctttcaagttgccggctacccggctgcegtagacagagtgaagtctg gtagtttgtgtttatttatttatcttggccagcagagagaattgagtttgcatggagact gtaatttcattctgtgagtgtaagatcacgtccgcgttcctagcgaccggttttgtgatg tgggcagtgccgtgctggtaaatgctctgtgaggaaggaacgatggtgggatttgtcact cagtcgatttccctggtgtaaatgctcccaccacggccgatttcaggctgccgaagtgga ggggttcagtgaaggtggagttgggcaagggcgtacacggtcggcttctgagagttggtc cccccgcccaaccctcccctggagatgggatgtcaggagacctggttccatttgtttttt tgcctgagcgtccgggggtggctttgaggacacctgtcctccttcacaggggcactccgg atgtagtagcagggagagggtggaggggcggccaagggcgtgagggagagggtggagggg tggtgtgagggtgcaagggagagggtggagagggtggcagtgagggcgcgagagggtgga ggggcggcatgagggagcaagccacctcgggcacaggtgaaggacaggtgtccacacctt gggtgcccccgtcctccctctcctcatgtcctaataggtctgaacaggaagttacattta gggcggctgtacagtgagttttaaataccttggtccaaattttcaaacacgtatcgttag cgtttcccctgttgctggccccagagtgttcggttcactgggtggagcatgctctgagcc cctggaggtacagggattttacgggaggaggggtcgcttcgaggggaggtggctgcgtcc atgtctggacggaattactcactgcctgtccctccctgcagcctctgttccctCC'tCaCC
agtctctgattccagctctgggctcagccagtggtctcaggacccccaccacattcatga aaattactgtggtcctcaaagagcttttgggtacgtgggctgtagctgccagtgtgaact gtactgaaaatttagaacgaggaatatttattcctcattaactctaattaatgtatgatt aattagattaattctaaaataacccatcggctgttaacattttaatgaaaagtgactatt ttcccaaacaaaatattcggcaagagagtggcaacatttttgcatctggttgagcagaac acggttgagccatcacacctgcctctgcgttcaggctgctgcagtgttgggttaagattg tgaggaaatccagtgtgtgaggaggcttggggtgaattccagtgtgtcaggaggcttggg gtgaattccagtgtgtcaggaggcttggggcgttttaacagcttttcctctggtaaacgt gggtattcttctttgatatttctctgaaactcggcacgtggtcatttcttacatgtcagt tgaaacatggaatctgaaactgtattggtgtcactttcctgcagttaccttaaaaatceg ctggtctcttttgcgctcgaataggtttcttacgcgtgcgtgtgttttaaaaatcgtatg ttggccgggcgcggtggetcacgcctgtagtcccagcactttgggagaccgaagtgggca gatcacttgaggtcaggagttcgagaccagcctggccaatgtgatgaaaccccatctcta ctaaaaatacaaaaattagccgggcatgcatggtggcggatgcctgtaattaatcctagc tactcgggaggctgaggcacgagaatcacttggacctgggaggcggaggttgcggtgagc caagattgcaccactgcactccagcctgggcgagagagcgaaactctgtctcaaacagca acaacaaaaaacatcgcatattggctgttaggaaatattgctccactgggttctgcaggt cttcctaagcgcagtggaaaattccccccacgctcatgagggcgagtgtgaagaaggcag gtgctgtccgcttcggattatggtcatagcttgcactcgcggetcccctgcctggtctct gggacccccaggcatccccagacctccctggcctcagccagttcccgccgcttcaccata tggcagaacacatgcgcggccggccggctcacagatgggcgtccctgcgtecggcccacc cgcctgcggtcctgtgtgctcaccctgccctggtctctgcctggactgtggatgggggtg agtggggcatggaggcgttetgcacccaccagctgtcagtgccagccacctgcctgccca gcatcgggtctgtgtggcagcaccttgtcagcaagtggaggtcagatgtggggtcagctg ggcgcagtggctcacgcctgtcatcccagcacttcgggaggcctagccgggtggatcgcc tgagctcaggagttttcaagaccagcctgggcaacatggcaaaaccccatctctacaaaa aaatgtaaaaattagcctggtgtagtggtgcacacctgtcgttecagctcctcgggaagg ctgaggtgggaggatcgcctgagcccaggagttcgaggctgcagtgagctgagattgtgc cacttcactccagcctgggtgacagagtgagaccetcttaaaaaaagaaaaaaaaaaaag atgcaggtcaggcacagaagcccgacaggctgctcccaccccaacatgaccgacaaggtg ctgtgtccctgccctccctgtggctc gcgggtagggggcgattcctctgtcagctgggt r _.
gaggagtagagaggcagctgagtgggtatttatttaaagggaagacaaggacgtagactg tacggctctctgaaacttcagcaacttttccgagacacgttgtaccatccgccctacctg gcgtgggcgtgaagctggtagcacacagaaggtcccggagcaggagctggccccgagcca gcagctttgtgccctgtgttaccggatettcagaatgcgcctccagcctgttgaccatet tactgctcacctgggtccgcagcccgccagataccaggcttgactttactcctggcgggg ctagggecagaacccagactggttgctgcgcacggtgctttttgccaaacctcacatttg ttggttgcgtttttcacaactcttgtcctctgaagatgcetgctcagagcccatgcagcg ccacgctggaggggctgaggatatggggggccctgttctcagagcecgtgaggcaccgtg ctggaggggctgaggacgtcggggggccctgttctcagagcccgtgaggcaccgtgctgg aggggctgaggacgtcggggggecctgttctcagagcccgtgaggcaccgtgctggaggg gctgaggacgtcggggggccctgttctcagagcecgtgaggtacegtgctggaggggctg aggacgtcggggggccctgttctcagagcccttgaggcaccgtgctggaggggctgagga cgtcggggggccctgttctcagagcccgtgaggcaccgtgctggaggggctgaggatatg gggggcccgggcccggctcccctctcacaggcaggtctgcacccatgggtgggtttggga ggccccggtcttactgtgttgatgcagagaggcacttctctctttctctcgctcccttct cctgtctgggttggcatcatcccaggagtaagagctgtgtcttctcccctccctgttgaa aggaatcttgatcctaatgtgaactcaaggattttctaaaaactgggtttattatcatcc tttttttttttttttttaaattgagacggagtcttgctetgtcgcccaggctggaatgca gtggtgcaatcttggctcactgcaacctctgcctcccaggtttaagtgattctcccacct cagcctcccaagtagctgggactacaggctcctgccaccacgcccagctaatttttgtgt tttgatagagacagggtttctccattttgcccaggctgatcttgaactcctggcctcaag cgatcctcttgcctcagcctccctaagtgctgggattacaggtgtgagcctccaggcctc agcctccctaagtgctggaattacagatgtgagcctccgcacctggcctggaatcatcga tttctgtcattgttc:gtcttgaggctctggtcctcccaggtttggctggcaggggccttg gcgagcggctccccccatgctacccgcttttccatcaggttttgtgtgttgctcgcatcc gggcagcaggctctggcatcccctcggccctttctgctccaggctggacctggccgtttc tecacggaacttggcttccttcggaggagggtggacttcagaaactaacctgcctgctgc tcctgggggccgtgaggctgtgcccggtgggcggtgggccaggggctgcatggggattcg atgtgcagttcccgcggcagctcccagtgccgcaggctcttctcttctccacttctgagt ggggtctccatctgcacagcgtgagcetgttcgctcgtgtgctctgccttegaatgcgga tgacacagcttcagagccgeggcatcgtcaccagggcagcagacccagccaggccagggc ttctcagcattcttttgtcctcagaatgcctcctgccatgcccatgcccttggagagcag tttccagaagttaacttggattcgtttattcatttgttgtctttcgtggggttatgctgt cagtatgatggtcagttggctttatttgtttctgtttgcatttgattttagtgtatttcc ccattcttttatttattttttttgagacagaatcttgctetgtcacccaggctggagtgc agtggcgcgatctcagctcactgtaaccactgcctcccgggttcaattgattctcgcacc tcagcctcctgagtaactgggattacaggcacccaccaccacacccagctaatttttgtg tttttagtagagatggggtgtcaccatgttggccaggctggtctcgaactcctgacctca agggatecacccacctcggcctcccaaagtgctgagattataggtgtgagctgttgcgcc cggcccccattcttgtttattttacttacctttgggtggtgaggcgecacggctcaccgt ggcaacagctggcagtgcagccccaccacgcagagagctgcaccagcacctgtggatggc atcccgaggtgccaggcgaaccctggggcttctgtgtctctcctacaaccttcgctccca agggtttttaatgatgctettatttttgcattaattgggttgtatcccatcacctggatg tgattaccgagaggagtatagcaggatacccgagtaatatgtgtgcgatgccagcagaaa gacgtgaagagagtaaatgaataacaggtggttttgctctgaagtgaccttttggtgggg gtggcgggggaggttaaaaccttcctgctcccctaaccgggtacccactaacagaaaatg cccgactctggaaaggagtccccggaggcccctgaggaggaccagcgtctggcctgtccg ggcaccgggggcagcatccaggccctcgggagccaggcaggtcactgcctgcacccgggg aggcctggcttcgaggctgggaacactgggacggcgtgagggacaggctgctggtgcctg gcgcgtgctggccgcctggacactcagtgaagacggtctttgttttgatggcggcagagc ccatcctgaatagcggctttctctgctgtgtgggtgggggcctcgggctcggatgctgcc tgagttggggttttggttttacagtttcccactcgtgtaactttaaggaggccactcagc agtgtcctcacctacctggcccagactccgcetccctcatctggataacgcccagcacac CtgagaagaggClCagCtCtgCCCCCgtCtgtCCCtCgtCCtCCtCa.Ctg'CtCCCtCCCC
cttgcctggatggtgcgccccatggggtctgcacgcccctccctccgcctccctgttcct cccctgcagtctcagctcggaggctgcccctttccatcgtgggcttcctgggaaccaaat cectcagctttggccctggttgcatccttagggctgaaaatggtgcctgggacccagcag ggctccctggacatttgctgaacgtcctcgagtccttgagtgaagatggctgtggcgagt gattgccgcgtgactcagcctctccatcccacgcccagagcggcttccggaggtcccaga gcccgggctccaggatgagcccagcagagtcttcccgtagacaccatcatcctgtgtgga _..
atgtcacctctcetttctaggtcaggctgtgggagcttcggagcctgaccaaacccaggt catgtgtgcacagctcagctgcctggaggcecctcccaggeggcggcgtctcttcactca cagactccagctggggctcagcgcaacatagcaagaccccatctgaaaaaaacacaaatc agtgtttctggttgtgaaagcaacacatgttcactacagaaaacttgacccatagggcag gatgtcagaaaagctcaaattgctcttgettgtactccctggtgagcctgtcacttttgt tttattttgttttgttttcegagagcatatcgtttttaatttcattctggtcttctatac tattagtttttatagaaaatactagtgatacgaggttagaatccctccctgtcatcagct aataatagcagtaacaatggtgccagttctgttccgggctcatcgtttctttttaaaatg gtggagcttactgcagtagagtgttttccttagccggggtcagctctggttttagaactc atttccctgttcgcaaggtccctgggcagagttcggccgggcgatggcagacgccgatga ggaaggacecagaggtctctgtttctggggcctgcatgggtagaaacgtgggggtgacgg tgtgagcatgaggatactcagagctgggaagacttgagggtcggggttggggacagagac ttccaggaggcagggecgtctctggtccgtcggggtctgcgttcatttgcttcagcctct gtgaggaggcaccacgaggggtggcctgtaaacaaggaccctgattgctcgagatgctga aggcggggaagtccaggcaaggtaccagcagatttggtgcctggtaaggactggttcaca gccagagccttctcagagtcttcttcacgtgataaaggggacgaacaaacactctggggt ccctttgaaaagcactattaatcccattccggaaggccacaaccttaccacctctcaaag gcctcctgacaccgtcgcctgtgggtgaggatttcagcgtgtgaattcggtgggacgtaa acactcaggtcacagtgctggggccgctgtagcaacgtaccacagatggcggctcacacg gcagaactcaattctctctcagcttgtgtggtgatcccagctactccggaggctgcggtg ggaggaccacttgagtgcaggagtttgaatgtagccagggcaacatagcgagatcccatt aaaaaaaaatccaaacaaaaagctttattctctgtctggagaccagcgtcegagagctgg gtttcggcagggetggttcccggaggccgtgaggagcccgggccaggcctgtccccttgg ctggtggagccgtctcttcttcacccgggcccttcctccccgtgcggccgtgtccacgtt accctctgttatgagaacagcagttgttttggatctaagtctgctgtaatgacctcactc acttaactgattacatctgcagtgtcctatgtgtaaataagggcatgttctgagctcctg ggggtcaggacggcagcttggattccgaggggattcagttgcactcatgcagaggccctg ggggctgcaccttggcaaggggttcccatggcctggccggtctgcagtccttgtagtcag ctgcacccagccctcctgcagaaggggcccgtgcacccatggttttgtagccgtcaggga gcacctgttcagagggccctgctgaccgaggggcgtgggctcagcactgccagggcccgt gccctgtgtccccacaggatggtgctggccgtctcaccactgaggggatgccccccagcc ecctcaccctcagctgctccttccaggagcttaaggcccctaaagtctgccccggtccct ggggtcagagcccaccctgggctggttttgaagaaacaccagtgcttctccaaggaggcc ccgtgcacatgtagaaatgaagccctcgtcctcccacagctgcatgcccctcctgcgctg cgtgtgtggttttgctcatggcacctggcgtgggcgccctgggagcggcagcegggggcg tctcggagagagccagtgcaggggggaccccacaatctgggaggccatggatcctggttg tgggtttttggttttaacatttggtttacttattttcagacttttttccaaacaaatggt ttatccatattaatttagctctccctgtggaatttgtaggacctcagttttcttgacatt atgatctaagcagattattgaacacacgtettaaatatcatcttttcaaactgccacatg taccatcatatagatgtgctttaataaagaggtcagagagctgtggcccactgtagttct tgtttgtttttttgagctggagtctcactcttgttgcccaggctggactgcagtggtgca atctcggttcactgcgacctccacctcctgggttcaagcagtgctcctgcctcagcttcc caagtagctgggattacaggcgcttgccaccatgcccggctaatttttgtatttttagta gagacgggttggggttttaccatgttggccaggctgctctcgaactcctgacctcaggtg atctgcccgtcttggcctcccaaagtgctgggattatagaagtgagccaccgcgcctggc ctgtttgttttttaattgtggtaaaatacctataacataaaattcaccattttaaccatt tctaagtgtgtagttcagtaaagtaaattcatgctgcacagccaatctccagaatttcat cttgcacaacagaacctecgcagtcccacctgcagcacacaggagttacgatgtctcgcc gtcctcgctgacactcccgactttctgttcctggccgtcctcttggggcgaggcagtgcc cagtgtgggtctagtttgcctctcccggtggttggtgatgttgagcctctcacgectgtg gccgettgtgtgtcggctttggagaaacgtctgcacaggtcctttgcccgttttgtaatt gagttcctcgtttctgtggttgcgttgtcctgtggggtggttgacctgcacgcaccgtgt gaactgatcccacttgttecatgcggacccaccgattaccaggtgggagcagcagggggc gtccgagggecctgaccccaggcgggaggacagatgcgcgtcetgtgttggggccacgga gttgtgggcaattgtttctttttcttttactttctttggtatcttccaaatctttataaa atctttataaaaattatttaaggagaagactcatgtagaatggaaagcgtcgtgccagac agtgcttggtacttgcaagaatggccgtgtccccaggagccggtggacgaatctgtcctt gctgccacccgtgcggccgcagagtgagacaggagggaceggcaggcatcgcgcttctcc cctagatactccggccatgccagccgcccccttggctccggccccgtccatccagcccct tcccagggctttgtcccctcacceccgccgccctccccctgttttcctacgggaggcgaa tccttgatgagaggaggaggccgggaaccctgceccctctgtgtgaagaggagggcagcc cctgctgctttgtagggaaaccctgcccaagagaagccccagctcagcaggacggagccc ggcgttcccgcctcagggtgcccagagagggcggggacaccctggctgggacaaagtgcg cagctctacecctgctctgaaatgcccgggactcggccgcgccctccccctttttcagag caacctgtgggccctggcaaggataggcctcaggcaaaggaaaaccaccctcgttttctt agcttttagattttaaaaggagcagtggggccaggtggacttgaagctccgtgggtttgt ttaaggtataaattcattgagcttgaagatgttgtacgtggaagtgaacagaacacacat aatttattcatggattttagctggcctgtttttgtacaaagggagcttttaaatttaatt atttttaagcattagaggatggtgtatccgaggcagctggaggccetggtcttcactgtg agcagggagggcccttgggacagggctcgggaggaggggccgggtggacccctgcagggc tggaggacactgagggcctcagatcaccacacagtgggcccagctagggggtgaccctga attccagtcccagcggacacatctcttgccttcagcatagagggccccaggcctcgggcc ctgcctcagttgcctccacgatgtcagcttccaggtgtggggaccgggtgccacctcacc ccccagttacacccacacgaggccgcggtgcccagtagcacagagatgccacgtgatggg tggttttcaacaggaactcaagagaaaagttcatgettgtgaggacagagctgcagcttt agccctgagagacctggcgggagaggaggcagatggcgagggccccaccggcagagctgc tgccctgaaaagcacctcctcctggtggacaccaggtgcatggtgtggtcaggtgtggag tgtgggcccgctggcctcgctgcttcctgcgccetgtttaccacccctcaccccctggcc ccagccttgctcttggcgggcggctagtgtcctctggccgccctggggcaggtcagaccg ccggggtgtggagtg~gggtgettgcetttttctgcctgaccctgcttcgtgtggggactc tgggacgctgtgacttggctctggcctggtccagcccccagtgtccacttctctggaagg cgaaaggcagggtgggggtctccttgatgtgggactggaagctgctcagccagtctccct ggaaaaggtcctggtgacagtcactgctcgctgcagtggctggtgccttcctcaaaggtg agggtgtccgggtggctgttggtgcggggccgctgggacctgtaccctctaagttgggac ttcagccccgcctctgcccecaaacgtggtgggctgagatgggggaggcecttggaaggg cccagaggaaccccagggcctcacagaggacgtgctgtgtacggtgcctcctccctgcgg cctgccccgcctgtgcttggagctgcatcgggcacagcctgccttggcgggcacgggacg agccgaggatccccgcgtcgacgtggaggtccgcggccgtcagcgttgcagccctcggcc gggcactaagggctgagtgtggggccagggcagagggagccaggccagcagctccaggcc caggtggaggaagtgctgcctgacacgtgtgtctgctccctgcggcacgtccacagcacc tgccagcccactttgggtgaccctcctgtttgtcctgtectagcgcagccacatcccttg ggagcctgcttgtctctagaaccttctgcctgatgcacaacctcagagccctccgtcgcc atccctcccccgtcccgggagcagcccccccacttecacctgtettggacgggagctgga agggacgtggttccagtcctgctgtgccaagcctggtgacccgagggtacccttggcctc ccggectgaactcttctcctaccatgatggtgcctgggatgetgtgtggtgeccgtgggc agtggeggaggcagtggccccggctegttgaaccttgggcactgcccattctgaggcgcc cgctgtgcccggctcgttgaaccttgggcgetgcccgttctgaggcacccgctgtgcccg gctcattgaaccttgggcgctgcccgttctgaggcgccctctgtgcccggctcgttgaac cttgggcgctgcccgttctgaggcgccctctgtgcccggctcgatgaaccttgggcgctg cccgttctgaggcgcccgctgtgcccggctcgttgaaccttgggcgctgcccgttctgag gcgcccgctgtgcccggctcgttgaaccttgggcgctgcecgttctgaggegcccgctgt gcccggctcgttgaaccttgggcgctgcccgttctgaggcgcccgctgtgeccggctcgt tgaaccttgggcgctgcccgttctgaggcgtctgctgtggcccttaccgtctggcttctc tgctggctcttttggccttggattcatttctggagctgcagagtcacttctcttagagcc tggttttggccctctctctcctgcctataaaaagccctgccctgggttccctgctccatg ecagttetctccctgcccccgccggcacgacacggacactggtgcecgagtgatgcctgt gggtgatgcagacactgactgtcaccccagccccccatgtgctgctccgccacaccccag gccccgtagcagggtggtggtttgggcagctgggtttgctggtcccctgggagtccaagc aacatcaccactgggtcccagatatgccgtctccctggggcacctgtgcttctggtaccc agggtggagtctggttgtctcctttccagacccttctaggtctgcgttggcctggctggt ttccctgaggttccctctgtaggggagggcctgccctcctggcaggggcccttgtgtgcg tcctgagetcaccgtggttttggaggtggctgggcagtggcgggcagagccccatgctgt cctctgcctttgaggtgggcacggcacacgtgagagctgagcattggtggaggaggccac aaccggtgcccagtggttgagtcgetggtgcccaccgagggcecagggagtgagggaccc cctgaagaggtagctgggagccagaccctcctcecgtggatgccttttcaagtccctgtc agttgttcagagaagagggggaggattcgcgctttgcgtcagatgcgtgcgtcctgcatg ggtggtgccggccggctgtgcccaaagtcatgccctgcccctgtetcccgcagcctggca tgggctcacgtccgtgtgcttgtccagcctccactcgccacagctcccctcccctcccct CCttttCCCtCCCCtCCtttCCgCtCCCCtCCtCtCCCCtCCtttCCgCtCCCCtCCtCt __ .._. _ _ .._ tCCCtCCtCtgCCCtCtgCtCCCCtCtCCtCCCttCCCCtCCtgtCCCttCCCCtCC.Ctt.
. _ _...
CtCCtCttttCCCCtCCCttCCCCtCCCttCttttCCtttCCCCtCCCCtCCtttCCCCt CCCC'tCCtCtCCCCtCCtCtCCCCtCCCttCCCCtCtCCtCCtttCCCCtCCCCtCaCCt gtttgactctgctgtgccaggggccagggcagggetggcccctcactctgcggagtaaat gggtgtgggggccgggcctgtctgggatcagggcagccaggcagggtctcctgcaggagc aggcatagtcccagggagcaggcagctgcctaggaaggcagtcaagcagatggggacctc ggctgccccaagactggcccggggctggtcctccctgcgtctggectctgggtgggtggt ggtggcttccttgtgacttcatccctccgatcgggcaggtggttttgtgcagtgtgtgcc tgggaggcgcacggcagcatgatcggtccctgagtgtcacggcagcatcagaggccagtt tggcatctggagtagctgccaccgagagaggcccagccgccaggcagctgggagcacagg tgtcggcatcccactgggagcacgggtgaggtgcctcccttctctgggcagagtttcccc agttggtygtgtagacgccaggaacgcggttgtacggacttcgtgaggatctaacacagc agtgtgtaaaaacagcgccaagcgtgtcctcggtgggcgctcagaggcggttgtgagcag tgcagatgctgttggcctagttctgacagggtggcccaggggtctccccgtggcatggca tggacggtggcagctcctgtggtcatcactgccatggtccggagcggccctgggctctgc agcaaggcggtgaatgtggagctgageggtccgaatcagggtctgggttgctcgttcaac tcaggaacttccccagattcctgagttttcctctagccgaggtcaggggcagccaaggga agggtcagecagctcatccagacctcgctctgcaacagatctccagcctgggttgccatg aggcaccctggggaggactcaggacgaggccccttgaggctgaacctgagacctaggaaa ctccaggtgggtcctaacagggcttgtcactgagcgtaggcctggacacggccctgtggt gtctcacccacgggcaccagtcectgttgagcaaggtccacgcagccctttgttctggac ggagctgacgctcaggccacagactccgactccattettcagaggcttcatcgcctgcac aggaagagaggectggagataccaggttgtcttggggccacagctggcccttggcatggc tggggagcagcaaagcagttcattaggaccagggctgaccataccagtgtccatgcccag aggttctgggttctgccctcttgctgtcgtccggtgcaggccacatggccacctgggaag gcctgggtcgtcgtcatattccgagtgtgaccaagagttcaggggcccaggtacctttct gggcccctctcagggtctttggaaaagtccagaatgagctgggctggtggagaattcagg aggtgtggccagtgcccccctgtgctctcagaagcaggggtcactggcgagagggctggg tggcceggcgatcaacctgaaggcattccttacctgcccttggacccggtgagccagtga ctggcgtaggctttcaaacctttcaaaccacttctcetggagccccgtgttgtgtgcgtc cctcagcccatgcaccccggaaggcacgcctcgcacccagctgtagagccccatgttgtg tgcacccccagcccatgcaccccggaaggcacgcetcgcaccgtgctcctggtggggccc gtgccaggggggcccaggctcctggggacagtggcccagga.cttgggatgttagaaataa attttgggtgecgcaaaagaaatagcactcgaacataaatttaattttctcagcaaggca attttacttctatagaagggtgcgtcttgcagatggagcaatggcgagagcacacctgaa cgagggaygtggaggtctcatcctaacgcagccagtccctgctgctgtgtggttcccctg ttggctagggttggaccgcacagtctaagctaattccgattggctattttaaagagagta gcagtacgagccggagtggcggggtgaatagtttgacgggaaggatggttacagaacagg tgactcaggatgactaagaacagagcaggtgacaaggatgactaaggtcagagcaggtga ccaggagtgactaaggtgaccaggggtgactaaggacagagcaggtgatagaggctaggc aggggttgtttactgaaactaggggcaaggatatgtaaagtacaaggaagttaaacttta gaatgaagaacaaagaatggggatgtaaccatacggatacattgcttetttggagaggag ctcagaattcattatacttaacaatttacaggetaaaacctttgaagaggaatttattat gttctacaggagcggtgccgctggcctgtggcttctgcagggacaagtagtggctgtggc cgggaggcgttcggcagctgtgcttcagccccggccccagcttcagctcttcgagttgct ggcttctctaaggcctgtcctgaagtggcctggagactgctgagttacttctggaatctg caccgtgaaagtgaaacctggaccatgatgtgaggctggtgagagggtgccctgccgtca cccecggccttgtagaaaactcattccaatggecctctggttctcactcaggaccaaata gtgatggttttttgtttgttttcgttttgttttgttttgttttgttttgttttgtttttt tagacagagtctcgctctgtcgcccaggctggagtgcagtggcgtgatctcggctcactg cgagctccacctctcgggttcacaccattctcctgcctcagcctcccaagtagctgggac tacaggcgcccaccaccacagttggctaattttttgtatatttagtggagatggggtttc aCCatgttagCCaggatggtCttgatttCCtgaCCtCgtgatCCaCCCaCCtCagCCtCC
caaagtgctgggatgacaggcgtgagccaccgcgccgggcccaatagtgatgtttttact gctctgggcctgatcgcatgcaccgttgtctgtgctgtgacttecgtcgttgtctgtgct gtgacttccgttgttgtctgtgctgtgacttccgttgttgtctgtgttgcgacttctgtg ggatattcgttggagaaggagccacacagctgtgtgggacccggcactccttcatcacca tcatccagggccacggacaccccctctcacaagtcgctgggatatgaaattagggaataa atgggaattttcagtgcgatgcagctggcgctaggatcctcctcagtgtgacgtctgaga ccttttcccagctggagccctgtcattcattcattcattcatcccatgccaggctgggcg __. ._._ . _ _ _ _,... __gc gccagaggcacaatccggaacc_gccc,cttgctaatgggcggaccagtgaaagcaaag _.
cgggctcgctgtgcagaccaatgattgacagttccagggtgtgatggacacaggcggctg ccaggaaggagccccttcagaagcagtgggcggggcggggtggggaaggccgtggggagg agtgacttccagatgaggctcacaggactgtacccggagggagggggcagcaaggaccct gtgggcagccgggggcacggcacaggetgtggctgtaggtgtgggtggtgcccaggcatt gacagaggggagctcactggacggggcagcgtggaggtgagggtcgggtgagggcccctc gggagcccctggccatgttagttgcacatttcatgactctttaaggagttagtgaggcct gggtgtgacctatttcccgttccaattaaacaggtcattagtecgtgtcgtgetaaagca gatcactcgcaaggaatggaaaacccttgaaatacgttttttaaatcggtgaaagtgaga aacegatgcctctgtgggaaaagaccagactccagggtctgcaccctcagagtgatgagc tgcgtctgttaggggtgacctgaggtccctgctttgaaccagcttgttgaaaccggaagc catttctcatcttctgtaagagcctgcagcccctgtcagatgccagccattceccaggtc ttgctgacactgtcattaggattcctatgagggccagtggggagacagctcagtctcggc cctgcttccgaccccaccaccacccccaaatgcatactgctggcctttcctgggtttaat tttattttgcagtggtagaggttgttttgctaaaattatttcaaaatctgccttgtggaa aaacgcccacgtcaaggtgaccatctgtggtaaccgagaattccttggaggcagcgtctt caccgcctggctaagcggatggcacaagctgccagccagacctctgtctgtccctgccca gaggccccagctgccccttcctccaggcacctccctgatctctggagtccaggttttgtt cccaaggtcctacctttg~tatctaaatgctgtgtcctctecccggacgatctcctccagg cactggctctcaggggccagctccccatgggcgatgatgtctctgatacaggaacttatg ggtaccttgcaagtttgcacagaaagtggageccgtctgttccttctggggtgtacgagc ggggcctcggggagcaggtgcaggacagggcacaggaggaacaggcacggctggtggtgt gcagtgaacagcagtggtcacaccaggtggtggctcccgtgggacttttgaggccggccc agccctgagcaggtggggtctgcagaggcctcgtgggttggaggagacttattcagaggg agttttggtcttgctagaaattgcatgagatgaaagatgacattttaattctatcattga ggcatagtctttccaacacaccccctgaggtgtgagggaggctgtccctatatgatgtgg tccccgctccttcaggctggggctcctggccagttcatctttcgtcctgtgtctgacttt ctctatcatttctaaaatgactaagacaatttattttgttaaaaaaaaaaaaaaaaggcg ttaagatgattetactttgtagagggatcccaagggagcgtctcctctgggactggccct gtcccccatcttgttttccctctaaacgacatgtgagttcccaactcttgattttagttc tgacaactggagactttattcccatacctttttaaaactttttaaaaggtttaacttcaa ggagataccattccttttgtgtatttggttactaaagctgtcttgcatctcaaatgtgat ttaagaaatcaagcaaaatgcactggccacgtcctctcagtagggggaggccagcgggca tctcccctcctcgccccttctctggtggtctcactgatgtcccccggcccccagccctcc ttcctttctttcccttgactttgtcctcagactccagggacaacccctggtgcgagacat cctgttgctgatttacttgttctctcatttgtttetgtgtttgttccatttctttcgttc attcattcattcattcatactcagctgcggagaccatcagccagtctgcgttcggcetgt gtctgccactggctacagggcccggggcaaaggtcttcaagtgccctgggcttcagttcc ccttcctggagaatgagggtgggagagtacctcccctgggggtttgcgaagatgacatga gcccgtgcatcctgggtctggaccgcatctgatacttagcaggtacttagcagcaggtac tgagtagacacagtgetccacagcaaagatgtgtggcagaggcgtagtggatgcgtgatc gagacgcacagtagacacgcaaggatacacggcagagatacgtggtgggtatataatgga tacagcgggcgtggtggatttataacagatatgtagcagatatgtgataggaaccaggca tgctaatgacaagtcaggaatgtcacagaggactgtgtcttctgggggtcctggggcctt ttcacgaggaaggattgcaggtggggctttggaaaaattgtccaatttccateccctgtg tcctttccccggtcaccgctcctacccagtagcaggtggagaaggtgacttccatactgg gggccaggatcaggagcagccacatgccagagegggtaggcagcccctggtgectgcctg gccctgecccgacctccacaccagttcagccctgtgtcctgcccaggatggatgggtggg taatttattgattcattcatttccagggtctcgtgtgggctttgtgaagcctagtacacg ttttttattgcgttttttttgtttgtttgttttgttttgttttgtttttgagatgaagtc tcactgtgctgcccaggctggagtgcagtggtgcaatcttggctcactgcaagccccgtc tcccaagttcacaccattctcctgcctcagcctcccgagtagctgggagtacaggegcec accaccacgtcccgctaattttttgtatttttagtagagatggggtttcaccgtgttagc cgggatggtctcgatctcctgacctcgtgatccgcccgccttggcctcccaaagtgctag gattacaggtgtgagccaccgtgcccggccctcgtttttgtttgttttactttgttatga gtaatgatagatttctagaaacttcgtgtatttttttctccactttatttcaactttgta gaaagagatctaaaaatgcaagtctcctcccccaacccccaactctcctgcgtcacggat tggttcagaaccaggagacacagggcccagaaacctaggggctggaggggccttaccctt tggactcttgactgtttttatattctggcccctccccccgtctgtctctctctcaagaga cagggtcttgctctgtcgcccaggetggagtacagtggtacaatcacggctcactgcagc _._ . tgggCtCaagCaagCCtCCCaCCtCagCCtCCCaaCtagCtgggaCttCaggCgCgC3CC_.
accacgcttggcta~.ttttttatttttagtagagttgggggtcttgatttgttacccagg ctggtctggaatgccccaagtgattctcccacttcgcccgcccaaagtactgggagccac cacgccgggctagactgtggggtttttggggggcaagaattgtactcatatctctgtttc cacagtgggtcttacactgtggacaaacagcagctgatgttctcacccggccttgttcta agaggactccaaaaagcaagtcgtagccccagtgactgggaaaggcttccccgggagagc ggccgacacagctgccgcagtagtaagggtttatttatcaaaactgatttatttatcagt tcaagacacagttacacagagtgtgggggatggttcatcagcagctggcacgtccagtgg cgcgtgtgcctcgggaaggcctgggagggggacacaggtgctccgcggggaaagctgccc ccaccccagcccaaagaagccttccaagctccatcagtcatgcagtcatgtacttttcct catcagcacaaaccccgcttccttgaagagaagcgtgaggctgggcacggtggcgcgtgt ctgtaggcctagctacgagggaggatcgcttgagcccaggaggtcgaggctgcagggcta tgattgcaacactgcactctggcctgggcaacagagaaagagagagaggactgtctagaa gggaaaacagggatagcaaagtagatgggaaggaagggcctctggggcggcgggtgagtg ctggccgctcccctctccacaagctgctgtggtctctgggggctgcacctgaggcggcag tgggaggagaggggtgaagggcaacgcgcccccgtttaaacacctcctggectggacgcc agctgttcacttgtaatcactggtcacectgaagagatgggatggacccctgcccaacat ttggctcaggtgtccacacagatgacagcaccgcacgcagacgggagggagcttctcacc acataatgaggttttctggggagagcaggggaggggggtcttccaggatggtccagaaag gtcttgagcgcgcctgtaaggagactgtctcggtttccgtggcggctctggggcaaggcg gggtgagcaggggctgaggcttgcagggtttgaactttccccagggccctcatcacctca ctgggatgtgggcgggaggggagcgggtcgtctcaaacacctccagcagtcgaacatcaa aaagggggtccaactcttggttgcgatttctttggctgaagcctggactcctagccccac gggctgagggaaggttacggctggtggttggatagacgccagtgcttgccccagagctgc aggggaagaaggtggcctgaacctcagggcctctgtgtccagttcaggggccagtacagc agcatcggtctgcg~.ggggtatgtgttctagaggagtgaggggacagacaggggagcccc agaggcatccagtggcgcgaatggtgggaagggccctaagaggggaggctgggaggggac aatcccaggtggcaggggatggccgcgatgaggccctggggtggagcecaggcagggagc atecaggggaagccagtgtgggtggggactgggaggagagagggaggctgggcctgccct ggcgaggggtggtcagaacatcgctcggtgccagacaggcaggacgcagcgggctggcct gcggggctcactgctgccccccggggccgagcacgaaagggagagttggagggcgcttcc tcgccgggtgttgcggtgtgagcggggactggtgagtgtgtgctgtcttcagagagagaa gagcagttttcagggtgagtagcctttattcttcacacctcattacacagcacccaggcc ttttattcaggagggcgeggceggcctcaccccgacagccaccctggcttgttgaccttg atctgtgacagctcccctgtgagttcagacttctcaaggacgcttgcatagccaacattg ttgagaacgagtaaccccttatcacagcacacgtctgtcgtgccatgaagcaatttccca tccctgtggctttgaaggcataagtcactgcgtcactgccatgctgttccttccaaacct gctcgtcaggagacagctcttgcgctgtgtaccggcactgccgcccagcaggtgacccca gcagctggtttgtccctgcctgggggtgagggcctgcagggtgtttgtagacgcaactct tgaaaggcectgaggttggggcttggtcatgagggtgcccggggcccatecgggagtaga agtaagtgcactaggcatttggccaagggtcacgttaggccttatttatttattttttga gacagtctcactettttgcccaggctggagtgcagtggcgtgatctcagctcactgcaac ettcgcctcccgggttcaagcgattctcttgcctcggcctcccgagtagctgggattaca ggcacctgecaccatgcgcagctaatttttgtatttttagtagagacggggtttcaccat gttggccaggccggtctcaaactcctgacctcaagtggtccacccacctcagcctcccaa agtgctgggattacaggcgtgagctgccactcctggccaggtcttttttcaaataaatgt ctaagcaaaatgaatttggggtgaagtagtcacagagctgtcaggaggagcagggtggct gcgtgcccctgggaactgccgtgggtgatgaccaggtgatgccgggaaggtcactttcag acacatagttgtcatcgtcggatgagaattattctcaggtctcaggtgggaggggctgcc caccaggcctggatgaggccecacccccccacacacacatgctgggaccacgagtggcac cccctgaggatgagggggctcctgcgtttgtgccctgtgtgggaggtgccacctcatttg catgtggcecttccacgtctcctggccatgccagacaggtcctcaggattgttgggagat gagggcctcgcccaggacttcgatggggtgtccccccagccccctgtggctgatggagca gcctgacattttgtggacacaaagccccctagagccagggaaggacagggccggacccag agccagggaagggaggtggagctccagccaaggcatccaaacatcaaaaggcagaactga gcggcttggtacttgaaaagtttttattaggaaaaatgccaaactgacagaagtagagag aattacatagtgaggcctcgtgcacaccctgcetggctcctggcaacctgcactccagcc gatacctgtgactctcagcaagcccctctagtgggcgaggacctccacacgtgtcgccag gccaggcgactctcagcaagcccctccggtgggegaggacctccacacgtgtcaccaggc caggtaactctcagcaagcccctccagtgggcgaggacctecacgtgtgtcaccaggcca __ ggtgactcttcagcaggcccctccggtgggcgaggacctccatgcgtgtcgccaggccag gtaactctcagcaagcccctctggtgggcgaggacctccacgtgtgtcaccaggccaggt aactctcagcaagcccctctggtgggcgaggacctccacacgtgtcaccaggccaggcga ctcttcagcaagcccctccacaegtgtcaccaggccaggtgactcttcagcaggcccctc tggtgggcgaggacctccacacgtgtcaccaggccaggcgactcttcagcaagcccctcc acacgtgtcaccaggccaggtgactctcagcaagcccctccggtgggcgaggacctctgc acgtgtctccagaggccaaagcagaagaaaacgttagcacaggagtcacttgacttcacc aaacgcagccaggattgcggtttctccggctcggctgtctcagttgtttaagagagttca tgcttttgagatcaaagttaaaagaaggcctgtgcctcgcagggcctgctctgcctcccc cgtgtttcctcggggttetgcgtctgtgaccggggtgcggagcactggtgtgcagttctc tgtctcgtgattcgtgtaacagtgagtgctgectgcaccaacagccagctgccttccgtg gctgtgtgggctcctgtgcggaggccgcccetctccctggccaagcaacactgaggcggg attgcgtcctccctctcctgaggcaggtectgctccagacctgcttttttcccgcacgtc acgtgtcctgagacccctcagtggatgegtcctctctccttccacggccgcacacactcc cgtgcccgttgggctgggctgactgatgcatgtgggggctccgtcccatctttttcaact acagatggagctgcggtgggaaaacgtgtgcagatacctcccattttacttttgtgctgg ggcttttttgggatcagttcctagaagtaggggactgggtgaaaggctgatcaccctcag acaccgaacccctggaggaaacacagggagggaggatgagccctgcgaggtgcaggcctt cttttaacactgaccttgggttctcaggactgccgaaatcccctctacccgggctgtgcc tctccggcctgtgcctctccggcccttcggcagtgtcgagggagcccccaacacccagca gcatccagggatttcccccagggcagtgtcgggagcccccaacaccccaacagcgtccag ggattccccccagggcagtgtcgagggagcccccaacaccccggcagtgtccagggattc cccccagggcagtgtcgggagccccccaaccccggcagtgtcaagggagcccctggcagt gtcaagggagcccccagacagtgtcaagggagccccccaaccccggcagtgtcaagggag cctgcctccgtggggtgctgccagccttaggcctgggccagtcggggtggttggatgect gttctgggggtagagaagtcaggtagcccagggcccgcactctcaatagaccttcagaga aaaggcatcgaggtaaatgccgcactcgagtacccgtgtgatctctgggtggggccatga tecttctgggcgctggtccaagcgcgtggtgaggccgtcctctcctgcagaaccccggcc tcttcgcccctgeccgctcacctgttetgtcctgetcacetectccaggaagcctgcetg gccttctccatgctgatgggcgtggccccttgtccctgcagccatgcattgacctccgtg gctcctggaggccaggccacgtcctcatcccctctgggtgagtgagaggcacagcetggg tgcgtggggccgtggcggctccgaggcgccaccgctgtgtcctctcatgagtgggtgccg tccaggtctgtcctgggetggctgcgaggaggaggttggcctcgcgcggccatgtgcgtg acagtggagacatcgccagcctcctgcttgcacagctgacggcagcccctctetctecag ccatgtccccaggactcttgagtagttggcctggtggccgtgggagaagcaggccccgag tccccagggctgtg~.gcgaggctgtctgatgtgctccctggtcaccaccccctgcctgtc cgtcttgcctgggcagatggaggtggatgaacttcctgcggccgctgtaacagtggccgc 9~

cactggggggcttaaagcaacacgcatttgttagctcagcggtctggagggtgcgagtgc agatggagctcactgggccaaatttagtcaaggcaccagctgggtgggttctttctgggg gctccagggagaccccgtttcccgccttctccggcgtctgaagccgcctgecccttggtg cagecetgagtcaccccagcetctgcctccgtctcacgtcaccgcctetgatacagccgc ccceccatccctcttgtgaggaccecgcaatgacgtgggcecacccagatcatecaggaa catctccccatccccacgtccttcacttcatcgtctgcaaagtcccgtatgccacggaag gtgacacagtcttgggtcccgggacttgcatgtggggctgtctgggttttgcacagctga ccatgggtgcttccggatgcttggcattggaggtttctgtcctctgetggaaggattcct ggagtgagggcagcagagggcacccagatggaggcactgceggacgcgcaggggcgatgg tcggggggcacctgggagccaccttccettgtctctggggggtgacccttgaccttggtg gcctcagttttctcatctgtaaagtggtgcacacgatacctgctccgtcctcctcactga attgtcctgagatcaggtgtggtcgtgaatattaaacatgtggattgcaaccctagacag agctcccttggacggttgagcagatgcagccaggtgtgggtccggctgtgggcggagggg gtcacacggggccgagtggcttcagcgagagtccataggacatggagagtcccggecgtg gtgaggacacggggttgcggcagctcacgcccactgcagtgtccggaaggcggtgctagg tccacctcatttacggggtcgggctctcattctccccattgtacagcccagcctgtagag gcaggtgaggtccaggccatgggcctgtgggccgtgccacatcgctcagattttgtggtg tcggtggtgggagccgccggggaaagccgtcatcctggagccgggcgagagagggccagg gcagtggggtggactccagaaatgtccagtagcagaattgccagacctggccattggctg gggtgttgagggagacgtctccagggatgtccagtgtctcccagtctgggcaagcggagg agccggccagcatgg~gccatttcatcggggccctccctgggggcagccaaggacctaaaa ccaatgggtcccaaccaagaggatcccagaggtgagacacagaacggccagggctgaatc cggggccctccctgggggcagccaaggacctaaaaccaatgggtcccaaccaagaggatc .__.__ _,._,._._.,ccagaggtgagaaacagaacggccagggctgaatctgcctccagcgggggccccgggcgt gatcagagcaggcaggacctttcttccctctctgcagctccggcactggcttcctccgtt caggcttcatccccggtcagggggctcctggtcccgtggcagccccgtggctcctgggtc gcagcttcatgggggaaacagagactcctctggtaccagggtcccctgaatctecggagt cccccaagtccattgagtccactgggcccgaagagggaaacagagactcetctggtacga aggtcccccaagtccctggagtcccctgagtccactgggccctcgacacccttgggtcac ttgtccaccctcacaccatcgctggcccagggaatgggggtttggatcggecttggtgac tgtgggcctctgcctgaaaccctgtgagtgtgggtggggtgggctgggtcctgagagagc tgggagcagcggagtgaagggggctggggtggggctggtgacagtggagtccctgtgggg ggcagggctggtggacagtagagtccctgtaggggctggtgacagtggactctgtggggc cagggtggggctggtggacggtgtagttcetgagagaccgagccggaaggtgagggactg gaagcttgcacacgtccctgeggccttcccctcgggtgegaggcctgecatcctgagctc ccccaccetaccecgtgeccgccctgagggcgggacccaggccagttcacacagcatggc gaggtaagggctcaggatggaaggcaggaggaaagttgggcctgctgcacccatgggtat tgcggcagggaaggcgaggaggagccgaggtgggtgctgggagctgtggggctggctgtg cgtgttgggcctaactcgggctgagctgaggttactgagccctcaggagggtgctgtggg aaaagaaagaggcagagaaggtgtctttggaccacttaggggacggggagggaaccccac ggcaactgtgaaggtctggggcacagccagggagggtcccaggttgacagggacaggcgg ggtgggggtgcaacatggaggcctggggctgagcetccgagaagtgatgggcaggatgag ggggccagaggggatcacgcaacaaggggtgcaccttggtggtctgggtgtctccagaga agctggttgtcaggactcaagaggcggacagggaggggctggggttagggaagagtgtgt ggcagggggaggaag~ggagcctggttgccgggtcacctggcattgggagctgtcccctgc ctgctgcgccccgcctgccattgttggagttctccagtctgggctggtctggatgaggaa ctggcagggctgctgccggcctggactcaggaccctcaccctccagcccgcaccctcgac tccecaccagccagaccctctgtcctggtgtggacagcacccacatcctggctccaccct tgtttcttgccctttgacctacagcctcaggacgtgcaggagggaggtacgtaggcactt gtgggtccggcctcctgaccgaccgtccatccaccaccaggcttctggatgttcacccat gtgggagagacgggtgtcggggaagggaccacagcttcctttcagaagacccgggaaggg cagtgccgtgtgccagcctcccagttggcaccttcctttcaccttagtcgtcttcgaggc gatgtttcctcgggacaagtcattttcatgaatctgctgtaaaacgtctcccaaactcca agtgtttcccaaactgagtgaaaatcgctgcagaatgtggtttccagcagagcttttccc etetccttcettcacctctgcctgggttacagggtgcgggttccaggagtetgcctagaa ggcaaaaaacaggctttgcttagaatcccetaaattgctcataaaacacagtgtttgacg tttatgtgtagacatgatccttatgtgggttaagctgaggcccctgccccagtgacacag aggcctcaaacggcacagtgcaccttctgtctgaagcagccggegaggcggcccgcgaac ctctgacgtgctccattgcaatgaggatgaacgagcctcaggcggagggtcagcctggaa cccetgccccgtgaacaccagccagcttcatgctgaggacccctcagtccaacccagagg cccatgctgaggtcccggcatgggggactgtggggtgcagccgccgcttggagtggaggt gaatgggaccccacacgtttectcctcgttctctggatgcctgtaaccatcacagtactc aaacaaggaagaagaaaaaggtccttgaaacttgctggagttgcagttccgtttttttgt ttgtttggttggttggttggttggtttttttttttttggagacagagtcttgctcttgtc gcccaggctggagtgcagtggcgtgatctcggctcactgtaacctccacctcctgggttc aagggattttcctgcctcagcctcccaaatagctgggactacaggagctcgccaccatgt ctggctattttttttctatatttggtagaggcggggtttcaccgtgttggccaggctggt ctcgaactcctgacctcaggcgatccgcetgcettggcctcccaaagtgctgggattaca ggcttgagccactgcgcceggecccattttctttacatttgtgacttacagtcatcagct gaaggaaagacagtggcttggctagggcctgcccactgctggccgaggctggccgggtca cccaggtgcctgcccctcctgctctggagccgggcactgcctgagggcctgcagcaccag tcagggccccgggggatccctccagggtctcagttctgactagcgagtacctcgattcat gagtatgttttttaatgtaaggttttaacgtaaggtttaaaaaggcagccgecccgtttc ctccccactggtctcgecttcagcagtgatttgtggtgactgtgacgttctcttcggtgg gctgcctgtggatcgccaagtatgtgctcctgctgettctacctgatgtctccccatett gggctttgaggggggctcatccggggcattcatattttctgcccgagttcgctcctgacc cagggcaggtggaagccagcaggtgaggaccagggtgtcagccagaaactcggaagtggc acagaggcagcatccgatagcccctttgtcagaggcgaccagggccttgagtgagctggg a,tggacttctcttatcctgacatcctggaagggggtgcagcctgcctgtctgtgtcccag ttgagttggcaacattttttgtctttcctcatgatgcacgaagtagtggtatctctgaga gccaatggcagcctagctgccgtggagaatgctggggggtgggtgagagttggggcacag aggactcatggggcagaggctgtggtccagtccttgtgggggtgactccagggatggcag gtgggtggtgtggccaaggaggagggaggtcaaggcactggtgttggggcagggagaagg _.gaccgcagtgcccatgtgtttgagggaggggagatgatggtgtgggagtgtagagagggc.._ ggggccccggccaacagcatccatgccctggggattgggtgccaccggtcaagggctcca cggggctggctctgggggagggagagcgggcgccatgttgtgtgtgtggtgcgtgtggcg cgtgggtgagggtatggccggctgcgtaagtttgtggaagcgttcggaatgctcaggaga taaaaacagcagagggctgcacccccccaccctcccaccccagcttttctccaggaggac gctccgtcgtggcctgggaggacgtggaaggagggaccccggatgcagggcaggttcgtc ttgtgtgttgagaacgtgctctccagggatctgtgttaatacaggtagcccaagcacagt gtccaatgagggaaggaacatttgaaacagaagagatgacttattttgttggacaaaaaa ggaatatggtggacattaattcttagaagaggttttatttgaaacaagtcacaaaaataa tcaaacagcaggttgactttggagttcagctcacgaaagttaagcttacagagcaaataa aataagctgaagaaaaagataagatgactgggcgcagtggctcacgcctgtaatcccagc actttgggaggccgaggcgggtagatcacgaggtcaggagtttgagaccatcctggctaa cacggtgaaatccagtctctactaaaaatacaaaaattagccgagtgtggtggtggacac ctgtagtcccagctgetcgggaggctgaggcaggagaatcgcttgaacccgggaggtgga ggtggcagtgggccgagatcgtgccactgcactccagcctggtgacagagcgagactccg tctcaaaaaaaaaagaaaaagaaaaagaaaaagctaagatgcagcaggtggagccgcctg ecgttgggtttcagcttttcttatggaaagaatgttacggcctgggtgcctccattctct gatttctttttctttcttgactttttaaaattgaaacaaaactccctaaaacatgaaatc tgaagcgttcaactccacgagtttttacaaagcaaactgcaccgcgtcacatagctgatc cgtgtgtagcttgtcctctggacacggggccacccccacacccegaggtgaccccaggcg taacctaccegtccccggccttggtgcctgcagatagttttgcttgtttcgagcttttgt cttgggatccggggccatccaccctgggtgtggccgctcagtcgggccectgtgtggggc tttcccgtggtgtggggtgcggttctgccgtgtecgtccccactgcggggctgctctgct ggctgaattctccacgtcttatgtatccaccctcatcttgcgaggcaccggggtcceggc ttttggccacagacatccgagcgccttctgttgcccgtagcgcatctttcatgtgggcac acccaggagtggagtttccgggaaacagacgtttccctcgcgtggccgcaccaggtcgca ctctgcactgtgtttctgcctccagttatgtggggttttctgcacccacagccactctgg cgccagctggttgtcctgtgtttccattcagctctgacatcaattacctgacgttagcgc agaccctgcagatgaagggctcattcccacaagcetgcccctacttgagagccagctgca agtgccaggtgacaacctggattctgaccaactggctgtgaatcgggggtgtccgtgacc ccttcctgaggctcaggtgggctagaatagctcccggaactcaggaaaacactttgctta gtgtacccgtttattagaaaggacagccacacggaggagctgcacgggaggctgaggtat ggggggtgcagagcttccgtgccctctccaggcacgccaccetccagcaccttggtatat tcaccaactcggacactctccagaccatgtcattgagggctttttgtggaggcttcgtga caggcacggttgattcaacagccagccactgctgattacctcagtctctcctgtctcctc tctggaccgtgggctgtgggacggaaagttccaacccgctaggcattccttggtcctgct gaagaccagccgcatcctggagctgtccgggctcccggctccccgtcatctcattagcat gcaaaaagacactcttaccacactccaggattcctagggtcagaggggctgcgcgccggg aaactgagacaaaggctgaatctgtgttgatggcacagtcactctgggtcgtgtgggaat tcccgatgcacetccttccagcacatggactgtcagagccctgcgttgtcgccagcacag cagatctgaaaggcactaggctgtggcctcgcgacggctgaggtgagctgcttetecgag gctcccgggttattggggaccctccttttaaaggtgcetgttccagtcttttgccccatt tcaaaattgggctgtcaaagaacaatgtcattggggggtccgtcttttttgttggttcct gggggctgtgtgtgttttagagacaagtgetttgattttttgtgttgcaaacagcttctg tcactccgcggetcgccttccactccatggatggtgtcttctgatgaacagaaagtaaaa gettactttataattagggcttttgcgtcctggctgtgtgtggggcctetttctggactg atctgtecectttgttttttgcccccatgtcgtactgttctgatttcttetgctttataa tcaccattggtaacttgtgttatgagtctccaatttggggtttttagttttcaaggttat cttggttattggctttttacatttccatacacatgggcttgttaataagccatttacagt tggcttatttgctttcaaaatctccataagacatttggattgcatttggatttcttgatc agtatgggagattagcatctttacaatactgaggtttccaatccgtgaacatatctttag gcctttgattggggtttttttggcaggggagttgcggggggcagacaggacctcactctt gcccaggctggagtgcagtggcatgatcatggctcactgcagccttgacctcctgggctc aagcaatcctcccacctcagcetcccaagtagctgggactacaggtgtgcaccaccatgc ccagctattttggcatttttttgtagagacagggtctccctatgttgcccaggctggtct tgaactcctgggctcaagtggtccttctgectcagcctcctaaggtgctgggattacaga tgcaagecactgcacccggccttaaattetttcaataatattttgtagtcttgtgtgtag cagtcatccacattttttgttcaaatgattccctggtatttcagtgcttatgctgtttta agccgtattacttttacagtttttttttttttatctttttgtttatagcaatgtgtaaag aagtgtgattaactcatttgtcttggcctctcctggtcccegtagtttgtctgtggttgc tccggaacctctctgtgcgctgccattttgtcagtgaccggctgtttgtt.tctgcctttc cttcagatgttgccttgttaccctggcactgttgatccttccaaaacagtatgggacaga agtggtgacagccacatcctctcgtgcctgatttcagggaaaagctttaagaattccacc attaagggtgctgtttgcggaaatactgtttttccttcgtaaatccccaccaacaaatta aagaggttctattttattcctagttgaaagttgttaatatgaatggtgctgaattttttc agatgctttttttccttcatctattgatgtgacagaacttttctcctttattctgttcat acgatgaattetatggattggctcttaatggtagaccgatggcattcctgtagtgtgcct cgtttggttgtgatgagttegcctttttatattttgcttgattcagtttgctattatttt gtttgttgtttttgcaactgtatttatgagagagattagcetattatttccttttttttt tttttttttttttttggagtctcactctgtcacccaggctggagtggagttcagtggcec gatctgggctcactgcaacctccgcctccctggttcaagcgattctcetgcctgagcctc ctgagtagttgggattacaggtgtgtgccaccacgcctggctaatttttgtatttttagt agagacagggtttcaccatgttggccaagctggtcttgaaccectgaccttaggtgatec gcccgccttggcetcccaaagtgctgggattacaggtgtgagccaccatgcctggccata tcttecttttgattgatgcttttatcatcatgaaatgtttttgttttttttttttttgag acagagtgtcgctctgtcccccaggctggagtgcagtggcaccatctecactcactgcaa gctctgectectgggttcacgccattctcctgcctcagcctcctgagtagctgggactac aggtgcctgccaccgcgcctagctaattttttatatttttagtagagacgaggtttcacc gtgttagccaggatggtctcgatctectgacctcctgatccgcctgcttcggcetcccaa agtgctgggattacaggcgtgagccactgtgcccggccaaatgttgctctttagatgaaa atattattgtcattaacatctgatctgtatgatgttagtgtgaccacaccagetctgtgt gtgtgtgtgtgtgtgtgtgtgtgtgtgtgtgtgtgtgtgatgaggggagggagggaaggg gacttagtgtttatatgctetattttttcatcctttcactttcttttctgtatattttgg aaatgactcttaaaagcagaagttagttatttttaatccagtctgaaaatggctgtgttt taaatgaaagatttagtccgtttacatttaatgtcattctgatgtgttacattgtagett tgtcatcttgctatgggtccttatttgtccggtctgttctttgttttgtccctctttctt gccttcttttggtttaatcagatgtttttattccactttcctcccttttattattatagc tttgttaagtaatacttctcttaatgttattttaatggctaccttagaaattatgagtca catccttggaacgtagcataaactacttttaccattttcttcaaaaccttataacagttt aattcttattttttccttttttttttttttttttgagatggagtgtcactcttgttgecc aggctagagtgcaagggcgcgattttggctcactgcaacctccacctcctgggttcaagt gattctgctgcctcagcctcctgagtagctgggattacaggtgcccaccaccatgcccaa ctattttttgtatttttagtagaggcagggtttcaccatattgaccaggctggtatcgaa ttcctggcctcaagtgatctgtctgccttggcctcecaaagtgctgggattacaggcatg agccactgtgcctggcctaattattcttctttccttattgttagtttgtgctattatttt atcagtctttgtgctgttattatcatgcctgtaaattctacgtgtatttcagacccacaa accaagtgttgtcttagacagtggtccttcagatttacccccaggttacccttetagtct 1~1 tcctgcaggacggcgcttacatggagaccagcttccttctgcctgaagtagtccctttag tattcctttcagcacagacttgtaattaattctttttatttcttttcttttctttttttt ttttttttgagatggatttttgctcttgttgcccaggctggagtgcagtggtgtgatttt ggctcactgcagcctccacctcccaggttcaagcgattctcctggetcagcctcctgagg agctaggattgcaggtgtgcgccaccacgcccagttgttttttgtttgtgtgggaaatgt ctttggcattetttctggagggtgttctccactctgtgtggagttctaggcaggtagggg gtttcccccaacaggtttttgtgttggcttggagtgttggtcatttctgtggtgagggcg ccttccagcctcactgccacccctggaaggcaacatctcttttctctgactcctgttaaa agtgttttcatcacaacagcagccttgtgaaggacagaggaategagaatttctcctaat tgagattggtagagcttcttgaatcagggacatgatagcttttgtc-tcttttggaaaata tcagcccttgacttttcgtttttttttttttttttttttttttttggagtctcgctcttg ttgcccaggctggagtgcaatggcgcgatctcgactcactgcaatctccacctccccggt tcaagtgattctcctgcctcagcgtcccgagtagctgggattacaggcacttgccaccat gaccggctaattttttttgcatttataggagagacagggtttcaccatgttgaccaggct ggtctggaactcctgatcatacatecaccttggcctcecaaagtgctgggattacaggtg tgagccaccgtgcccggccagcccttggcttttcaaatagcatcctgttctctctcccct gggacccccacacttcacacctgtgtgtctaatgtgctcttttttctgggtttcttctgc gttggttttttcccgctttgtgcttcaatgtggatttttttctactgttatctcttattt cacccaatctactcttaaatctaccctttaaattattaatttcagtcacttcatttttta cttttagaatttccatttgattcttttttttttttttttgcccaggatggcaatggcacg ctctcggctcactgcaacctccgcctcccaggttcaagcaatattcctgccccagcctcc caagcagctgggattacagggtcacactaccacgccccactaatttttatgtttttatta gagacggggttttgccatgttggccaggctggtctcgaactcctgaccttgggtgatccg _.._...ettgcctcagcctcccaaagtgttgggattacaggcgtgagccactgcgcctggcatcgt.
agttctctcttctggggtgggaatgtctattctgtgtccttcteacgtgcaaaatactgt cattacatcccaatcrgccccagaacccttaactcctcccagtgtggcgggggcagtcttg tctgaacaaggcatgggggagcctggaggcccattcctcctgaggccaagttcctccctg gctgtgggccagcataagcgaacaaggcgtgtacttccggaatgctatggactgagtgtg tgtctccccagaatccatatgttgaagccctaaccctccagtgtgatggtgtttggagac gaagcctttgacaggtagttagagtcatggcggtagttagttagagtcatggcggtagtt agttagggtcacggtggtagttagggtcatggtggtacttaaggtcatggtggtagttag ggttatggtagttagggtcatggcagtagttagggttatatcagtagttagggctatggc tgtagttagggtgacggtggtagttaaggtcacagcagtaattagggtcatggtggtggt tagggtcgtggtggtagttagggtcacggctgtagttagggtcatggtggtagttagggt cacggtggtagttagggtcatggtggtagttaggatcatggctgtagttagggtcatggt ggtagttagggtcacggctgtagttagggtcatggtggtagttagggtcacggctgtagt tagggtcatggtggtagttagggtcgtggtggttaggttcatggtggtagttagggtcac ggtggtagttagggtcatggtggtagttagttagagtcatggcggtagttagttagggtc acggtggtagttagggtcatggtggtacttaaggtcatggtggtagttagggttatggta gttagggtcatggcagtagttagggttatatcagtagttagggctatggctgtagttagg gtgacggtggtagttaaggtcacagcagtaattagggtcatggtggtggttagggtcgtg gtggtagttatttagggtcacggtggtagttagggtcatggtggtagttaggatcatggc tgtagttagggtcatggtggtagttagggtcacggctgtagttagggtcatggtggtagt tagggtcacggctgtagttagggtcatggtggtagttagggtcacggctgtagttagggt catggtggtagttagggtcacggctgtagttagggtcatggtggtagttagggtcacggc tgtagttagggtcatggtggtagttagggtcacggctgtagttagggtcatggtggtagt tagggtcacggctgtagttagggtcatggtggtggttagggtcgtggtggttaggttcat ggtggtagttagggtcacggtggtagttagggtcatggtggtagttagggtcacggctgt agttagggtcatggtggtagttagggtcacggctgtagttagggtcatggtggtagttag ggtcacggctgtagttagggtcatggtggtagttagggtcacggctgtagttagggtcat ggtggtagttagggtcacggctgtagttagggtcatggtggtggttagggtcgtggtggt taggttcatggtggtagttagggtcatggctgtagttagggtcatggtggtagttggggt cacggctatagttggggtcatggtggtagttagggtcacggctgtagttagcgtcatggt ggtagttagggtcatggtggtagttagggtcatggtggtagttagggtcacggtggtggt tagggtca.cggtggtggttagagtcacagggtagaacccttgtggtgggatttgtgccct ttataggatgagaggatgagacacaagagaggttgtgctgcgcctgtgctctctgctcca catgagaacatggtgagcatgaggccgccagcaagcaaggagataccccgccctgcaggt tccgtcatcctgactccagcctcggaaacatgagaaagtcaatgcctgtcacttaagccg cccagtctgtggtattttgctgtggtggctgagccgacggagacagttccataggtcttg attgtcctggtggccctgaaccccagtttttgtctccagtgagatgcctggcccggcttt ctgtgtgacctecgaagggtcagcagacgccgtgcatgtgcagggcttgggtggcgcatc tctctggcaacaccttctcttctgacgcacttgtctggtctcggatgectccaacgcggt ttttacttattttccagctttcgtcgattgttcgtgggaggagggttagactectegcgt ggcgtccctggccacatcctcagcgctgtgtcccctcgcagctcagttcetggttetgag ttattgtgactcagccgcacgtcctcccaggggccttgccagcctggctctgtgccgggc gctgggcaatctctgcctccagcctgggcctttgggtctgtttgagggtgggggacacgg agctcagcagtgaggaactcggagcagcttcttgttgttggtgttgatgtgttttgtttg ttttagtgaatccagaaaaaaaatttcttacatagaaaggagcggtatttggtatgaatt tatttgcaactgactgcttggaagttggcgtacatctttccacggaaactatgaaaatac eggtcagcctctcagtcatttcataaaatcttgattttgtattacaacaaattaggatat tttcagtagaactgattgtaaggccagactgttggaatgtaattccttcccaaacatctc tcaggggcactttcctgaacggctgctgacagcagcatttgaggacggtggggcggagga catcctggggggcctggcttcttgggaactggaggctttggcccttgtcccaccectgct cccctgaggagggaggcgtggggccctgggctggctgcaagacgtggagtgactgtgggt ccccgtggcccctgacatgctcccagggaacccaagaaaagactgagaccctgtggtgcc tcccgctttccatccgcattccatggcaggtgagtctgattattcgaaggaggctggagt gtgggcggagggcagcgccaggtttcccaatcagatttgctcagggtccctccagcagtc catgccgcagaggctgtcccttgggggcccacgcatcctagccacggcctcctcacgtcc atgcggggatttgcgccctggaaggagccgcccggctgcctctcgccaacatgcagcact tcccttcctttccatggagcacggttcctgtcccgggggtccatattggccactgtggga gagagtcgggcagctgaattcccgcaggtgggaatgccagggcccgagga~tgttgcccct gtcctgaaggctgtcgcccgatcgctctatccaaggctgccctggggcagcgtcacctgg gggtcctgcgggggcttctcagcacagcatccagcactgccacctagtgtgttcccgtca __ cgtctcctccccecgcctgcaccagg_caccagagacccagatgecaaggcctgtcagctt h._ cctcaatgggaaacttttcttcagtgaacaaagctctgttttatagactttttaaatttt cagctcaaaaaccaaagtctgccagtgttggtggccttggagggctggtctgctgecctg ggctgcaggggctgcccggctggggtcgtggtcggggcaggtgccgcccacaggttgttt ggctgcaggtgatgggcaggtcccccatcacgtgtccagaggtgggtgctgctggtgggt aatccagctcattacctgtctccccccagccgccttgggctggggaccctgccccgccga ccetgccatgcccacccccctccagcetgattgcgtgtetcagtcacatgaccgccctgg gcccgtgatgtcactgggaaatgccctcgtttgattggcttagaccccagatgaacaagc ccaaggtcttggggcatcagagccacccatgagggcagctggatgcagcggccacagcct gtggttggggaatggcattgcgcagctccaccacgaggggacctgaggcttggactgtga gactggcccaggctcgccacttgcccctcacccggggttgccttcccgagggccgcggac acctgagcagtccccatgccactgcattgtggcagggacacggccgcccatccctcctgg gtcccttatccacctgcctgtcccttcgtatcactgacaccctgatacccattgtgctgc gccgtgtggcccggtgcccacagggccgggttctgcctgttcctgggggtccgtgtgtcc cacgtgcctagacgtgagaggacggaagtcggcagagcttggctccctgttcgcccgact ggcgcctcggctgtgcctcttctgtctctcgagctcttctgtgccgtgtggttgcactaa gcagctgtggggaagggggaggttgttgcctcagtgggagcctgggctgtggctgccagt ccccaaaacagaccctgcgccecgggcaaccatctgcttcccgccacagtggtgcccaaa accttttccaagtcgtcttctgtgactttagtgttattcttcagtcacctttaaaagcat agcatgttt;tcaatcacatgttcagctgggaaatagatctgtggttagaaacgggaagtt tgagttgcaggcttgcgatccgggcaggtccctcagatggaggggctgcacctccactgc ccceeccacegccgeccctgccccacggccaccccagatcctcagacgcccctccctgtg ccttctcaccctctggtcctggctgggcccgtcccgccccacgtcccgcctcccactgcc ctcagcctctggaacggtgcctgcatggctggcactatccagcgcagaaggaatgaagga cttctgttcagacagctctgctgggagcgttctggcctgaaatgcagtgggagctctggt gcaggtgtagccgaggctcaggggctccacaccaggcaaataggcgaacggcgtctcccg cggctcccggtggctttttaggactctgcgttcgtgttctccattgtccctggcagcecc tggccagggtggcccagtgcccactatagagggtgcaggtcagtttgtggaccaatggcc aaccaggctgagtcaggtgaggtggggagtcccaccccaaaccccaaactccagtgtctg ggccacgggcagccctgggacaccttagctctggacacgaatttgcggtcattgctgttc ttgtgtctctatttgcctaggacatgctggcagctaactgggtgctggggaagcctggag aggaagccaggtggccecaggctcctggagctcagaatctagtggaaatcgctgcccagg gaagaagctccggagtctagaggtggcagcacccattttacctgcaccctcagtgacagc tgcaccctggcttctggggacctctgggcccaagggcacctcactgtctcettgtcctcc tggtcactgacctgggccaccatagaaggcacctggctatctgcatgtggcttgaccact gccttgcacccatccgggccccgcagggccgtcctgtggcactgctttgggctgtgctgg tcaccctgtgtagcagggccatgtccagtgaacaggagaggcctcaagtgccccctgacc tgctgccagggactcggcccctccctcaccgccaccgcacccaagggctgtcgcctgtcc cagcctgctgctccgagtttagtgttttaaaacgtgttttctacgtcttgtcagagtgct caaggcgcgagattgccatggaaactgagctccttagaattcctgtggccgtcctaatta tagaatctcaaagacacgcacagagetccttgaggttgtcggagttaaggctgaaagagg aggageggeccctgtgatceccacaattttgttccctgettgcttcagcagagcctggca cccagggaggtggcaggatgggtccccaatgggcacgtgacatcgagccagctetgactc caaagcctgacccgtgtggctgcaccgtccactgtgcgctgtccactgcaggagacccca ggctgtgtccacacgtacccccggaaggacctcctgctaacctgggcttgactttgagac cctgttccacagaggtagccgggggactcgcggtgccaggcccacagcctcctcgccggt agtatctgggggccaggggccgtttccagagcacactccccagaagggctcccttetcct tttcacagcgctgtctgtcgcttaggtcagaaataggcccatcgctttccaagcagaaac ccaaacactgaaaattcgactgtgacttttgaggggtggggaccgccaggtccccccaac atccctgcccgcgggcccagaaaggcagagtggctgccggeccgcgtgtccaggcccctt acactgagggaaccttctagtcaattgcctgaagttcgaaggtttggggggttttcgtgg ttgcttccgtttgttttggcagttgcagaatcccccgaaaaggtgggaatgtggattttt caaggcaggtgctcctttgattcagaagctaaggaggccctaagtgcagtctcaccttga gaaaaatatcaggccagtcctaacggaggggcgtcctgcagacacccagcctgcactcag aactgtcacggtcagaaagcacggtcagaaagtctgagaaagtcacggtgcagcagggcc cgagaggcaagacggtgacacgtgggctcctggaagaggcaggatggtgacacgtgggct ccaggacaggaccctggggcggacgcagacagtgggtgaaaaccaaggaaaggtctgaat atcgcttaaggtagccatggatcctgtctcattaattgtaacagtgtagcaggcgggtgg aagatgagagctgtc~~gggagccaggcagggggggtctctgggaactctccaatttaaagc tgttcttaaaaatagtctattaaaaaagacagttgagggcggccctgcctacagctggag t gaggttctagcaccaggcttcctctcagcctccataggcgagtagggaccaggcaggg ccttggccacagggaggcttctggttaccaggttctccacagcctttgcagtttccctgt gaatctgaaattacccccaaataaaaaggatgggtttttttgtttgtttgttttgttttg tttttgagacagggtctggctctgttgcccaggctggaatacagtggtgtgatctctgct cagtgcagcctccacctgccaggctcaggtgatcctcccacctcagcctcccgagtagct gggactataggtgcacgccaccacactcggctcattttttatattttttttatagagacg gggtctcaccatattgcctaggctggattcaaattcctgggctcaagtgatccacctgcc tcgacctaccgaggtagtggggttacaagcatgagccgccacgcctggccaaaaggtgta tttgttaagtacaggctgccctgctgtccgttatcccttataactcacctggtccctgct ttccagctggggactggcatggaccccatggggcttcccccatttcactgaggcaagacc cagatgctgggggtattgggtgtcctgcccaaccagggtccccagggccaggggctcctg gcgtgccttcccgtgggactccgcatggggggctgggagggcgaggaaaatgggaaacat gatgcctgcccaaaactcccacctcggagaccctgtgccagggttttccagagagaccaa accaatagggtgtgegtatagaaagatctattgtaaggaactggcttgttcatagagact tatgaagcccaaaatctacagggggcccagcaggctggagacctaggaggagccacagcc gcagcactgctgcttagggagctcagcctttgctctgtggaggcctttttctgcttgggt gaggcccacctgcattgtggtgggcagtctgcttcccccaaagtcagctgatttaaatgt ttatctcatccatactcaccctcatggaaacatccaggataacatttgaccagccgtctg ggcaccatggcccagccgcgtggacacatacagtgaaccattgcaggcccttccttggca cttggcatccacgcatatccccttaagceacactcagtctccacacagcagtactcccgc ctgacacactcggtctccacacacagcagtactcccgcctgacacagttcgaccctcccg caagcagtgccagcacacttggccttcccagaagagggccaccatcatgggctcggacct tccagctggactgcGgtggggtggggcgtggcetcgcctctgtggtctttgggtcacttg aatccccgcctctcactcattttcctttggtatttgcaaatttgtccccgtggcgcctgg agctgactgccgggtgccacatgtgtcctgcctcaagccaagctecaggcggcacccgtg agcaggeagggatgecagtggtttctcacetgggagtttetttgcaggctcagagctctt tgttcctttttaaaaatctgatttgaaggccgggcacagtggctcacacctgtaatctca gcactttgggaggccgaagtgggcatatcgectgaggtcaggcgttggagaccagcctgg gcaacacaggttggggcaactcccttccctaataaaagttcaaaaccaacccttaaagtt taaaaagtgagatgggatatttgaaggaggcaggtctgagggaaatgcttgaaattatcc tctctgtcectgtgctgccaggtcatttagttccattgttattcaacataccatttgaca catgctaggagcgcaggactcggcaatataaagcgtggtaatcgatggacactgccccca gcagccagccaggggcaggacttaagccccacccaactgcaggctgtcccccgccgctgc tagcctgaaattggattggttactgctgcggectgaaattggattggttatttgcttact ggaacatttttgtcacatgactgtgtattctaaaacaagatgttgtttttgtttttgaga gagtctcgctctgtcgcccaggctggagtgcagtggcgcgatcgcggctcactgcaagct ccacctcccgggttcacgccattctcctgcctcagcctcccaagtagttgggactacagg cgcccaccaccacacccgactaattttttgtatttttagtagagacggggtttcaccgtg ttagccaggatggtctggatctcctgaccttgtgatctgcccgcctcggcctcccaaagt gctgggattacaggcgggagccacegtgcetagtattgggtttgtttgtttgttttttga cttacttgtttggttctatagcaatggcaccatgtttctgtcacectagggtttgatttt tggtgtttctaagacacetctgggccactgcacatggctgaggtgggcttcgcactggct ctgtcttccgttggacgeccacacatcggtttatttatgcattctcttgtecacagacct tgaggtcatcagacatcttgaatgctcccgagcccaggggcgagcgtttctgagctttga cggagcagcagtggggctgccgggccctagggggagcaaatggtcctcgtttctgagctg cgaggctctcccagagaataagccatttctccggggcactcctgggcctcgaaggtgttt ggggctgcgggggattgatttgtgccgacccegcagtgtaggagacgcctgggcggcctt gcgggttgcttcgatggttctcggggctgagatgcttgtgtctctctcgggcgagacgcc tgctctgggcttctgttcctattttgactgctttttectcatggatttttcagtccagca tccetagccacgggccctttgtetetcatgtgtgcaggtgactcacggtgactaaaatct tctgtaattccttctaaaatgttttgccgctttgctgtccacgtttccacccttagtctc tgaggggcctagtgtgtgtatggtgggaagcggggtcagcccccgcctggaccgctgtga cagaaccccacagacagggtgacttacacacgacagaaacgtcttttctcaagttctgga ggcgtggggaccccatctccaaatacagccacattgggggttagggctccccacgtgaat ttaggggacacttcagttcgtcccggcggggactggggacgccgggctgtgtgctgtgtc ctgtgggagagtttgttcaccctgctggaggctccctgatgagccctggcgtctgctagg acgtcattctctttactgattgaactcgaaggatgtccagttggcgcattttcagggttt cccaggcgcactgggggtgggtcctgtgtgtccccgctccagccagcttcgacccccagc tgtgcgtcagtccctcagctccgccccccagctgcgcggccgtccctcggctccgcccca cagctgtgtgaccgccctgcggctccgcccgcagctgcacgttcgtccctcggctccgcc cccagttgctcgtcggttccctcggctccgccccctcggctgtgcgtc ggccctcagct ccacccccagctgcgcgtccgttcctcagctcagtccccaagctgtgcgtccttccctca gctctacccccagctgtgcgcecgcccettggttccaccccectccccagctgtgcgccc gccccttggttccaccccccccagctgtgcatccgtcecttggctccgccccgcactgtg cgtccatttttgactccgcccccggctgtgcgctcatccctcggctccgeccccggctgt gcgtccgtccctcggttccgcccccggctgcgcgtctgtccctcgactcggcccctcagc tgtgcgccactttctctgtggcccacagtacctccgtctccgccgcttcacacccttctc tttctttctctcttcagagagggttgttgggcaggcagagcatcccccgaggggacaagt caggcctacggactcctggagccaggacctgecgtaggctggttagggcaggatgcgccc tgtcttcgtgggtagagccacatgggggctcacccgaceccctcagggctgaggggcaca ggggccgaaagtgtggccgcccctgggggtctgegcctcttgtggagcccaggcctggcg cccaggtgggtggagtgtggagggggcacaggctgcacgaccccagcctggcctcgggct tgctgggagtcgcgtctgtggccggaggggcctttggtgtcaccaggcctctgtcaaacc ccaagccgcatcctgggagggctgggtgggctgagccgcccgctgccgtgaggcctcttt gacctgcgctcctggaggacccctgacttcttggtttcgctctgaatcttccatttaaag gaagaggagcaggttttaccatccgtgtggcctgatttcagcagtttccagtcagggcta gtcatttgcttgttttaaaaacattccgttacaatttccacttcagtatatttgtggcac tttcatttggttcatgaaagtcgcttttatgatggaattttataaaagcacaaagcttcc cattgtacgttccgtttctgaagattctgtttacacacacatccgtttcaaagagttttg gaggagcaaagtgggacacggtgttgaggaaggacaagaccagccgtctggttacaggct tggtgccgcctttctcataagaggcacagtccgcatgggctggactgtcaaatgcatgtt ataaagatgatgtttttggtaacttgcgaatggaaacgggtgcacggtcggtttggctct cctgccctgagatttattaggttaaaggaaactcgactggagagcccggggcctcgcgcc gcttgcgtctggcgagttgttgaagtgaagtcagtggcgctctgcaccttagcctggccc aggctccactgtggcgtccactcttcctcctctgacagtcatgtgtaaatattgaggccc gtttgaactatccctgtgcggaaaaaaaggcctgtttttcacagggctgcctggggagga ggggggtggaaaggaaaacaggcaggggacagacggacccggcctgcgttggcctggggt gacttcacggetccactgtcagcaagcggccgtcccgtggtggatcctgtccgccctgcg aggacacctggctccatccacacctgggcctctgtctccagccgcegaggccgtgacacc atgaggatcatgtgaggaggggcagagagaggcctccgggaggccgtcattccagccctg ccttccctgcctgggaggacgctgcggccgccaccacctggacgggagtggcetgtcgca gctgcaccctgcgtgggctcgtggetgccacgctgtttctttacacctttetcatatcct ttccagAATCTATCTACCGCCGGGGAGCCAGAAGATGGAGGAAGCTGTACCGTGCCAACG
GCCACCTCTTCCAAGCCAAGCGCTTTAACAGGgtgagtggcccccttgggactagtccct caaggggccttttgttacttttaaaagcaaagagagaggaggggaggcacgteccgctga gcccaggctgggctctttttggcgcccgagggcaaggttacagaaatgctttctctggtg caggatgaggctttgactagggctgtctgaggcgggaagtgccctccgggcctttccctg cgtggtggctgcccagtgaatgctgtctgtgtctgcctggctgtgtgactcttatcaggg ctcagggctcactggcctgaggccccagcctgcctgcatccagagtggggcggccgcatt ccatccgcatgtagcgccagggtgtgtgttttcagccgcacacagtgttgcctagtagct aagagtctccgtgaaccctggaagctccttcagccccatccetgcttgggcctctgtctt cccagcggccacccacgggggccctttccagaggacacttagcttattttccttgtttct ctttatgatgcttttctagttcctatgaaatgggtgattcagatgcttttgtaattgttc tgtttcacagtggaaggggaggtgtctgggtgtgccttggtggccctggagttggtccca cacagggagtgtcttgggggtgcgtggaagtatacagggcctgtccccactgcgggactc cacacagagcccctgacagcccctcacaggagcggtggccctggggctacctttgcattc cacactcacctgccacgtggcctcacgtgtcaacctccgctgggtgtacggcacctctgt ctcctggagcggcctcaagtcacctgcccctccttctactcccatggtctgccctctaga ccatcaggaagttctgttcatgtgagccactcctcctgcccctgcgtgtgctcggtccct gtcatgtggcaagagtgggtctggactcccattcctcttggggctaacacaggtgaggat gcaggacaagctcctgagtgactgaagaggggtgtggtgggaactaggctccaggagatg agcaggtcagcactaggaagacctggacattgcctggagagcccagaggacttectggag gaggaggcatctgatcatactgcctgggaggtcagtgcagaggagatgccaggagcaccg aggatgtggcaggcacgggagagtccagccagtgtctgggaggccctgaggacgaggttg gggacaccaggaaatggggagcctaggcggctgtgtgcttagggcaggtgggtgtgggtg aacaggcagtttggctcaggctgggactcaggagagtgtggctggaggtggccacattgg gaatatctgtggagtatggtgccagggagtgttgcagcacagagatcccgtccgcacccc agcccaccctggccgccttttctgaggacacacgttgtgagtcttctggggctgcagaac acagcaccactaactggcagcttaaacaatggaaacttgctctccggcagtctggggctg gaagtccaaaacgaaggtgtctttatgagtcagggttctccagagggatggtaccaatgg gatgcatgtacatgaaagggagttgattagggagaactggccctcgggcgcacaagacga agtcttacgataggccagctgcaggctggggaagaaagaagccagtagtggctcactccg agtccaaaagcctcagaagcagggaagccgacagtgcagccttcagcctctgccagaggc tccagagcccccggcaaaccactaataagtcceggagtctaaaggcccaagaacctggaa tctgatgtcccagggtaggacgagtggcaggaagcatccagcatgggagaaagatgaaag ccagaagacccaggaaaactgcttctcccacctgcttccgcctgctttgccccagccgca ctggcagetgattggacgccaccgcccacccacattgagggtgggtcttgccctcccagt ccactgactcaaataccagtctcagggcagegccctcatagacacacccagatgcaatac ttcaccagttctctaggcatccttcaacccagtcaagtcggcgcctggtgttacccatta cagtgccacagggctgcgccctccttcccccgcagccactggtagctgcgggcagccttg ttcctgtgctggcagaggaaccactcacctctgtttccgtctccacatggcctcctctgt atctgtctcttctgtcattctgcatgacggattagcccagagtgaaccctacccacccag tgacatgggccagggctccgggcagcacagggtgtggcctctcactgtgcagctttgagg agaaaagtccattctgccgatggcaggtgcagaccataagtgaccctccccctccccacc accaccagtgagcaaaagcttttcctttccttcctgcagacactggaggaaagggtggca ggtggacccaccacagccccgctctgctgtggaggtacagcccttctgggcgtgtgaacg agccagtttcacaaacacagaggccaaggcgagagtggcccgaaagcctgcaacctgact gctcagggagggcggctgccctgcagttcagcotgtccgattcccgcctaattgtgcccg ggctctgatctcgccacctgctcgtaacgttctctgtccggacctcagagecgctccatg tagtgcteacttcatgttaattgcaggaccactcagatcacctctgctgtcacttaaaag gggcatttcaggaggaaagcacttggttttgtgtgaatcagtaagacttaaaggggaaca agcacecaggagaagagagacttttccgtcctctttgttggtgaagcgaggatgaaagag tgggcatccgtcgetggggactgggctccccgcccagctctttctgtgcacttgaaagca ctgcccttggactttgagaaggaagcgttcagtgggggagccaaagggagagagecagcg aggttctgaagaaggaggtgaggaggggctgcctcctccatgaaggatggtgccgggggt ggcagggaagcccactcagtggaacagaactgctgggtcagagctggcccagggctgagc acttcttgcagaggagggaagggatcctccagtaaatcctgaggaggtgattggttaatt atcagcccaggaatggggggtgaggtgggtaggaatccaggctgctggctcccatcacag taaacggcaggtggattgaggttaaaaaaaaatcacagggcccggcgcagtggetcacgc ctgtaatcccagcactttgggaggccgagatgggtgatcgcttgaggccaggagttcaag atccatctggccaacatggtgaaacccatctgtactaaaaatacaaaaattagccaggcg tggtggcacgtgcctgtaatcccagctactcaggagtctgaggcaggagaatcacttgaa cccaggaggcgggggttgcggtgagcegagattgtgccactgggcgacagagtgagactc cgtctcaaataaataaaaagaagaaacctagaagctgtgcagatctctggagaaaaaccg ggcagtgaggaccagagggtctttagactcagccacacagaattttcagattttttcagt ttccaaattaaatgcaaaaaacatacaggaaaggggtttgtagcacgtaaaacccagaag agatccagacatctcacacttagaattgaagagctcctacacaaaggcttttggtaaatg ctgggaccgagaagctgagaaccggtgtgaatggttaatgaagtaagactgtaattgttt agagatgaggacagcatgacctccacaggtgatcagggaaacacaagacattttctetgt caacatcaaagatgttaaaagtaattaaagccggccgggegtggtggctcacgcctgtaa ttccagcactttgggaggccgaggtgggtggatcacgaggtcagcagttcaagaccagcc tggccaagttggtgaaaccccgtgtctactaaaaatacaaaaaaagtagecaggcgtggt ggtgggttcctctaatcccagctactcgggaggctgaggcagagaattgcttgaaccegg gaggcagaggttgtagtgagecgagatggcaccactgcactccagcctgggcgacagagc aggactctgtctcaaaacaacacaaaacaaaaacaaaacaacaaaaaagtaattaaagcc cagggttgctgtcatggggtctgccaaccctggggatgtgggacaggcatggaccctact ctetggaaatcacgcagaaatgtgcagcgatgttcccatcctgcctctcttcaaaagaaa tcacccgtcattcggaggtttgtgtatggggaagatcagctcagcattatttttacaagc aagagtgggaatcgtgtctggagttagctactccctttgctgtgaacaacccactccacc acgtggggtataaaccatggtagggacacgtctctgagctgtggctgctggagagccctc tgctggtggcacatagggcacaagtgccgcagggacagctgggtggatggcccaagactt tggcctttatcatgagtggacagaggagtgaccacttgggtccctggagaagaggctata gagagtgagggtggggaagggagatcagaagatgccatccatgagcagcagtgcctgtca ggtttggtccaagcagtgccctcaggtggctggcagaggccaatgcaattccttttcaag ccagcatcaaagaattcctgatgataaataaatcaggcatctgagctcgcaatggaaaac cacaaaacacagtgggaagcaggatatcctgagtccaagctggtaaaagcccagacagag gctccaaccatcagaataggtaagggtgtggcaggtctaaaacatgaaaatgggcgattg aaaatatgagcaggaggccgggcgcggtggctcacgcatgtaatcccagcactttgggag gccgaggcaggcggagtgcctgaggtcaggagttcgagaccagcctggtcaacatagtga aacactgtctctactaaaaatacaacaaaaatttagccaggcgtggtggtgggtgcctgt aatcccaggtactcggtaggctgaggcaggggaatggcttgaaccagggagctggaggtt tcagtgagctgagaacatgccactgtactccagcttgggtgacagagtgagactccgtct caaaaaaaaagaaagaaaatgtgagcagggaggccaggtgcagtagctcacacctgtaat cccagcactttgggaggctggagcgggcagatcacctgaggtcaggggttcgagacgagc ctggccaacatggcgaaactttgtctctactaaaaataaaaaatcagccggacgtggtgg caggtgcctataatcccagctactcaggaggctgagacaggagaatcgcttgaacccagg aggcggaggctgcagtgagccaagatcgtaccactgcactccagcctggggaacagagcg aggcgcgaggctgtcggagggagggaatatgagcaaggaacaagttggcagcatgtaaga cgtacttaaaacgtttttacccattaatctatgaattcctctgagtttctgagaatggaa acttggggtttaggttttatttttttaatgtcacatttcctgaaatgttactattcaaat atagatttgaaacaagagcttttgacagagcttgggcagcctcacttacaaagcacacac gtgaggtctctgtggtgggtgccaacccttggcagattcacactgcccttgtcagcagat gtcctggcctgaccccaggtaagggtggctccccacggaaaggaaccttggtcaatttgt tttttgtttgtttgtttgtttttctttttcttttttttttttttttgagacacagtctca ctctgttgcccaggctggagtgcagtggcgtgatcttgactcactgcaacctctgcctcc tgggttcaagtgattctcctgcttcagectcccgagtagctgggattacagatgtgcgcc accacgcccagctaatttttgtacttttagtggagatggggtttctccatgttggtcagg ctggtctcgaactcctgaccgcaagtgatccgcccgccttggcctcccaaagtgctggga ttacaggcatgagccactgcgectggccaatcttggttaatttgtaaagatacctggtgg ctgtgaatttggtcttaactaggaccgtagtgttgcagagtaagatgttaaatggtgacc tagagaaagccaaacacattaggcacattataccaaaagaacttgacttttaaataatgg ttttagaaatggaagctggtgttcttctgcgctgtggacgcggaggagaatggagcaggt ctgcacagccaaagtgcctcctttcactccagggtccaggcatccagcagccgaagcgcc tcctttcactccagggtccacacatccagcagccgaagcgcctcctttcactccagggtc cacacatccagcagccgaagcgcctcttttcactccagggtccacacatccagcagccga agcgcctcctttcaatccagggtccacacatccagcagccgaagcgcctcctttcactcc agggtccacacatccagcagccgaagcgcctcctttctctccagggtccacacatccagc agccgaagcgcctcctttcactccagggtccacacatccagcagccgaagcgcctccttt cactccagggtccacacatccagcagccgaagcgcctcctttcactccagggtccacaca tccagcagccgaagcgcctcctttcaatccagggtccacacatccagcagccgaagcgcc tectttcactctagggtccaggcatccagcagccgaagcgcctcctttcaatccagggtc cacacatccagcagccgaagcgcctcctttcaatccagggtccacacatceagcaggtgc cgactggggcaaaactcccaatgccggcattaagctagattggcccggaatcagaggtct tgggtgggatgccccctctcacccatccctccttcgaatagagcccacggtcctggtgtg gctctgtcatggctgggctgatgtaggtagcatgtgcagaggatgtggagtcggctcctt tttcctgtgacgaagttgaaagcgatgatgcatgtgtgttttcttacccgatgcccactg tgtgctgggcactgtcctaggtgctggtcatccggccccacccaaacaagtgggctgtgt gggcggggggagggtccccgggccctgacgtcecgagcaggctcttctgatgagcaggag agtcccgtagagggtctggacccectttgctcagccgcacctgatgcccacatgtgctga gggtcccggttcctcacgtgaactcagtgctgtattttctettcagtcccgtttcetcac gtgaattcagtgcaggcggttcacagtacactgtatttcctcttcttttttttttttttt ttttttgagatggagtctcactctgtcgcccaggctggagtgcagtgacgcaatctcggc tcactgcaagctccgcctccggggttcacgccattctcctgcctcagcctcccgagtacc tgggactacaggtgcccgccaccacacctggctaattttttgtattttgtagtagagacg gggtttcaccgtgttagccaggatggtctcaatctcctgacctcctgatccacccgcctc ggcctccccaagtgctgggattacaggcgtgagccaccacgcccggcctatatttcctcg tcttaactcaggtgtgaggtgagctctgtaataggaaggaaatttgtgaaaaatggtaaa agagggaaaagcatatgaaagggctgtgtctggaaagaatctgaattggaggctctgggc acatggtgacagtgcagatgcacccctttactcccaggaacactttgggcacttaggcaa ggcagaaaatgtecaagcaggtccegacaacattcattctcatgccttttgtaacattta aacgttcatgaaaacatcgccaaacaagctgataattaccatcattttggaattgttcag aaccatgaagaataaagaaggatcatttaaaatcttgaaaaatactgaacaaagaatact aagataattgcaggctgccatgtagcagttcaagatgttcatgagtccgagttecccttc tctgaggctgtcaggaggaggttctgtttgaatgaaggtcaggcagggggtgcccccaca cactctgcttagccctagacgggaccecaggctgctctacgcagagcgcagcaggagctg cagccccccagcccctgcaagccacggggccttgcetgaagcagcacctcgtcacccctg cccgatggcacctcccctgtgtcccctcatgcagagcagggttccaggcctctccttggg gccactggttcccccaaccttgggatagacccaagaggaggctctcaagcttgggcaagc ctggcgcccggaagggacaaggtgccggggccacctgttgcccggctcagtgtcctcttt tgagaaggtataggtgtggaaggccctgcctgtcctctccgctggcccctcagtgtggcc tgggcctgacgctctgttcccacctgcagagagcgtactgcggtcagtgcagcgagagga _...
tatggggcctcgcgaggcaaggctacaggtgcatcaactgcaaactgctggtccataagc gctgccacggcctcgtcccgctgacctgcaggaagcatatggtgagtggcagggctgggg aggcccggggggcacgggcggggtcggggcgtggcagccagcccattgtccaagcagacc ttggtgaccctgggttcttcaagaggggccgtggtgccgtcctagctctgggctgcagcg tgagactcaggcggcagtcttggataggacccatcttcctgagcccccacaagcccccgg cacactctgctcattggggcatgaggctcaggcagcaggctcaggtaggacgtggtacgc tctgctcagtgggtcggaggtaaggttcattcataccccagtcttgaaccagctcttaag gactgtggaggtgaaagccaggtctgacctagtagcattgggcacgctgaggctccgaac atctggagcctctecctggcatcccccctgggaagccatgcccagcctgtgatgagggeg gcaccttccctccgccatccccgagtgcttggacttgaagcatccaggcctttgggggcc ttattgacttttgcttattgaaggctgcctctggcatttecgtgtggccccctgcatccc actgaaccacgggggtgaggcctggactgaacattcaactccctgggccctgctgcagcg tgcagtgggtgtgtctggggagggtggcttgtctgcatcttgctgtggcatgggaggaaa ggcgcctgtggcagtgacgtgccctctcetctgttacgggataaagacagagtctggatc agggtgtcaccccaggatcaccagccacagggatgggggaccacgcaggctggtgcatgc gttggcacagtccttccagaggtccttcagetgcatctgccaaaaagcctgtaatgccct ttgacctcataggtccactttagcgtaagcaaatgagaccggccccagaaatgtggtcag ctagaggcggagggaggccagagcctgccacccagctgaccgccagtactggtggctcca ttatgacatatctgcaggcggaacccagaggcccttagaatggccccctgatgcttggtt actgacaggatgcagctttgggacaggggagatgaccaagcattgtgcaaaatatcccgt tgtataaagcacttggtggaaaggtcatggcctgcagtaccgagtggccacctccgtctg cagaatcataggtaatgtttatgttctttatctaattcagtaaaatagcataacaattag atttttatatactatattacagtatacccattgtaatgtgtaaatatgtaaatcataaat agtcttgaagtggccaggtgcagaggctcacacctgtaatcccaacactttgggaggcca aggtgggaagatcacttgaggccaggagttcaagaccagcctgagcaatatggtgagacc ccatctctacaaaaaaaatacaaaaattagccaggcatggtggtgcgcacctgtagtgcc cgctgctctggaagctgaggcgggaggattgctcgagctcaggaggttgaagctgcagtg agccgtgatcgcgccactgctctccagcctggatgatgacagactgtgaccctgtctgta aaaaaaagttcttaattttaaaaagtcacaaagtgtttacagaagctacattgtaacacc tgctctagcacttggtcatgctgecatctctgtgtctctccggcaggattctgtcatgcc ttcccaagagcctccagtagacgacaagaacgaggacgcegaccttccttccgaggagac agatggaagtaggcgctgctttcttccggccgggtagagectgggcatcacctcaccctg ctcacctetgecttctagccacgagtcctttctcagtcccatctgctctgcaggggtcat tgtcttcaagcctggccacccttccctggggctggggatgaggctctccagggcctcctc tcaatccccggcagagatgagcagggtgagctggccctccctggaggctgctgggcaggg atgcctccgtgaagtgctgttgtggttgcccaggggtgcagagcctcttcctctaaccag ctccgggagttctcgaaggcacttagtgcagcagccaccatggccgggcacctcccacaa tctggctgctgcacagagctgagccctatctggggaaagcctggcgaggtggctgctgca cacacagcgtggcagtggcatggtccttggatttttgtgagggtttgtttgttgtgggga aggacttgttttattgctatgaagcattcagagagagaactctaaccaccatttgactta caggtccgtgtttgaagcctcacacccagcccccctcaccgggggggggggagcaccttt tatttgttgcatgtgggtggtggggagggtgggaacaataaacaagcgactgatgatgat tttcactcgagccttttggcactgatatgcggactcagtggctgacgatactaatagtct attaccggtcgttgtttttaccgcttacagttcagatggaggtatatatacccacatcag nnnnnnnnnnnnnnnnripriririririririririnnnnnnnnnnnnntctCttttggaaaatatcag cccttgacttttcgtttttttttttttttttttttttttttggagtctcgtttttgttgc ccaggctgaagggcaagggcgcaatctcaactaattgaaatctccaccteccgggttaaa gggattttcctgcctaagcgccccgagtagttggaataacaggcatttgccaccatgacc ggttaattttttttgcattaataggaaaaacagggtttcaccatgttgaccaggttggtc tgaaactcctgataatacatccaccttggcctcccaaagggctggaattacaggggggag ccaccgggcccggccagcctttggtttttaaaaaagcatcctgttttttttcccctggaa cccccacatttaacacctgggggtcaaaggggctttttttttggggttttttttgcgtgg gttttttcccgttttgggcttaaagggggatttttttctacggtaatctttaattcaacc caatttactttaaaatctacctttaaaattataaattecagccacttaatttttaacttt aaaaattcccattggatttttttttttttttttttccccagaatggaaagggcacctttt gggttcattgaaacctccgcctccaaggttaaagaaatattcctgcctcagcctcctgag tagctgggattacggggccacattaccaccccccattaatttttatgttttaattaaaaa ggggtttcaccatgttggccaggctggtctcaaactcctgacctcaggtgatccgeccgc cttggccttccaaagtgctgcgtatatttaaagatacagttagataactt tgatgtatg . _.
caaacacatataaaacatgtataaaaccctcgctgccgtccagatgatgaacctgtccgt Ca.CCCagaagCtCtCtCCtaCCCdC3CCCCtttCtccccaggctgcagcagtCtgCtttt gggcctgtagattcgttgccttecttagagctttgtctaaatgaaatcctacaatatgtt cttcttttggtctggcttccttccctcagcgtcattattttgggctecttggatgcgtgg cgtgtgctgggcagtgttcccctgcgtggatgtcgcgtttgttcctccatttgcccgttg gagcgtgtggagtgtttccagttcttgactgtcacaaagaaagcggctgtgaacaattcg gtacaagttgttgtcgggatacaccgttttatttccctggatagatacctaggtgtggaa tggctggatcatatagtcggagctgatgttcaactttggagaactgccaggctatgtgca aggtgtgggtggcatttgttgacctaccaggggaaagtgtatatatctattgttactcct atcacccgtctgtgcacccttccgtaccctctctccctccccccctcagttcaccccttt CCCCtagCCCCCttCCCtttaCaCtCCggttttgCCCCCtgttgtgC'tCa.CC3CCCCgat ttttccccctctcctctttcgcctcgtctctcagtcaccaccccttttttecttattctt CatCtCttagattaCgCtatCaatgtaa~'~nnnnnnnririnnnnnnnnnnnnnnnnriririririri IlIlnnnnririririririririnnnnnnnnnnnnnnnnnnririririririririririririnnnnnnnnnnnnn nnn nnnnnriririCagttttCttgaCattatgatCtaagCagattattgaaC3CaCgtCttaaat atcatcttttcaaactgccacatgtaccatcatatagatgtgctttaataaagaggtcag agagctgtggcccactgtagttcttgtttgtttttttgagctggagtctcactcttgttg cccaggctggactgcagtggtgcaatctcggttcactgcgacctccgcctcctgggttca agcagtgctcctgcctcagctteccaagtagctgggattacaggcgcttgccaccatgcc cggctaatttttgtatttttagtagagacgggttggggttttaccacgttggccaggctg ctctcgaactcctgacctcaggtgatctgcccgtcttggcctcccaaagtgctgggatta tagaagtgagccaccgcgcctggcctgtttgttttttaattgtggtaaaatacctataac ataaaattcaccattttaaccatttctaagtgtgtagttcagtaaagtaaattcatgetg cacagccaatctccagaatttcatcttgcacaacagaacctccgcagtcccacctgcagc acacaggagttacgatgtctcgccgtcctcgctgacactcccgactttctgttcctggcc gtcctcttggggcgaggcagtgcccagtgtgggtctagtttgcctctcccggtggttggt gatgttgagcctctcacgcctgtggccgcttgtgtgtcggctttggagaaacgtctgcac aggtcctttgcccgttttgtaattgagttcctegtttctgtggttgcgttgtcctgtggg gtggttgacctgcacgcaccgtgtgaactgatcccacttgttccatgcggacccaccgat taccaggtgggagcagcagggggcgtccgagggccctgaccccaggcgggaggacagatg cgcgtcctgtgttggggccacggagttgtgggcaattgtttctttttcttttactttctt tggtatcttccaaatctttataaaatctttataaaaattatttaaggagaagactcatgt agaatggaaagegtcgtgccagacagtgcttggtacttgcaagaatggccgtgtccccag gagccggtggacgaatctgtccttgetgccacctgtgcggccgcagagtgagacaggagg gaccggcaggcategcgcttctcccctagatactecggccatgccagccgcccccttggc tccggccccgtccatccagccccttcccagggctttgtcccctcacccccgccgccctcc ccctgttttcctacgggaggcgaatccttgatgagaggaggaggccgggaaccctgcccc ctctgtgtgaagaggagggcagcccctgctgctttgtagggaaaccetgcccaagagaag ccccagctcagcaggacggagtecgacgttcccgcctcagggtgcccagagagggcgggg acaccctggctgggacaaagtgcgcagctctacccctgctctgaaatgcccgggactcgg ccgegccctccccctttttcagagcaacctgtgggccctggcaaggataggcctcaggca aaggaaaaccaccctcgttttcttagcttttagattttaaaaggagcagtggggccaggt ggacttgaagctccgtgggtttgtttaaggtataaattcattgagcttgaagacgttgta cgtggaagtgaacagaacacacataatttattcatggattttagctggcctgtttttgta caaagggagcttttaaatttaattatttttaagcattagaggatggtgtatccgaggcag ctggaggccctggtcttcactgtgagcagggagggcccttgggacagggctcgggaggag gggccaggtggacccctgcagggctggaggacactgagggcctcagatcaccacacagtg ggcccagctagggggtgaccctgaattccagtcccagcggacacatctcttgccttcagc atagagggccccaggcctcgggccctgcctcagttgcctccacgatgtcagcttccaggt gtggggaccgggtgccacctcaccccccagttacacccacacgaggccgcggtgcccagt agcacagagatgccaatgtgatgggtggttttcaacaggaactcaagagaaaagttcatg cttgtgaggacagagctgcagctttagccctgagagacctggcgggagaggaggcagatg gcgagggccccaccggcagagctgctgccctgaaaagcacctcctcctggtggacaccag gtgcatggtgtggtcaggtgtggagtgtgggcccgctggcctcgctgcttcetgcgccct gtttaccacccctcaccccctggccccagccttgctcttggcgggcggctagtgtcctct ggccgccctggggcaggtcagaccgccggggtgtggagtggggtgcttgcctttttctgc ctgaccctgcttcgtgeggggactctgggacgctgtgacttggetctggectggtccagc ccccagtgtccacttctctggaaggcgaaaggcagggtgggggtctccttgatgtgggac tggaagctgctcagccagtctccctggaaaaggtcctggtgacagtcactgctcgctgca _ v. gtggctggtgccetcctcaaaggtgagggtgtccgggtggctgttggtgcggggccgctg__r. _ _.
ggacctgtaccctctaagttgggacttcagccccgcctetgcecccaaacgtggtgggct gagatgggggaggcccttggaagggcccagaggaaccccagggcctcacagaggacgtgc tgtgtacggtgcctcctccctgcggcctgccccgcctgtgcttggagctgcatcgggcac agcctgcettggcgggcacgggacgagccgaggatccccgcgtcgacgtggaggtcegcg gccgtcagcgttgcagcccttggccgggcactaagggctgagtgtggggccagggcagag ggagccaggccagcagctccaggcccgggtggaggaagtgctgcctgacacgtgtgtctg ctccctgcggcacgtccacagcacctgccagcccactttgggtgaccctectgtttgtcc tgtcctagcgcagccacatcccttgggagcctgcttgtctctagaaccttetgcctgatg cacaacctcagagccctccgtcgccatccctcccccgtcccgggagcagcccccccactt ccacctgtcttggacgggagetggaagggacgtggttccagtcctgctgtgecaagcetg gtgacccgagggtaccctcggcctcccggcctgaactcttctcetaccatgatggtgcct gggatgctgtgtggtgcccgtgggcagtggcggaggcagtggccccggctcgttgaacct tgggcactgcccattctgaggcgcccgctgtgeccggctcgttgaaccttgggcgctgcc cgttctgaggcacccgctgtgcccggctcgttgaaccttgggcgctgcccgttctgaggc gccctctgtgcccggctcgttgaaccttgggcgctgcccgttctgaggcgccctctgtgc ccggctcgatgaaccttgggcgctgcccgttctgaggcgcccgctgtgcccggctcgatg aaccttgggcgctgcccgttctgaggcgcccgctgtgcccggctcgttgaaccttgggcg ctgcccgttctgaggcgcccgctgtgcccggctcgttgaaccttgggcgctgcccgttct gaggcgeccgctgtgcccggctcgttgaaccttgggcgctgcccgttctgaggcgtctgc tgtggcccttaccgtctggcttctctgctggctcttttggccttggattcatttctggag ctgcagagtcacttctcttagagcctggttttggccctctctctcctgcctataaaaagc cctgccctgggttccctgctccatgccagttctctecctgcccccgccggcatgacacgg acactggtgcccgagtgatgcctgtgggtgatgcagacactgactgtcaceccagccccc catgtgctgctccgccacaccccaggccccgtagcagggtggtggtttgggcagctgggt ttgctggtcecctgggagtccaagcaacatcaccactgggtcccagatatgccgtctccc tggggcacctgtgcttctggtacccagggtggagtctggttgtctcctttccagaccctt ctaggtctgcgttggcctggctggtttccctgaggttccctctgtaggggagggcctgcc ctcctggcaggggcccttgtgtgcgtcctgagctcaccatggttttggaggtggctgggc agtggcgggcagagccccatgctgtcctctgcctttgaggtgggcacggcacacgtgaga gctgagcattggtggaggaggccacaaccggtgcccagtggttgagtcgctggtgcecac cgagggcccagggagtgagggaccccctgaagaggtagctgggagccagacectcctccc gtggatgccttttcaagtccetgtcagttgttcagagaagagggggaggattcgcgcttt gcgtcagatgcgtgcgtcctgcatgggtggtgccggccggctgtgcccaaagtcatgccc tgcccctgtctcccgcagcctggcatgggctcacgtccgtgtgcttgtccagcctccact Cg'CC3CagC'tCCCCtCCCCtCCCCtCCttttCCC'tCCCCa.CCtttCCg'C'tCCCCtCCtCt CCCCtCCtttCCgCtCCCCtCCtCttCCCtCCtCtgCCCtCtgCtCCCCtCtCCtCCCtt cccctcctgtcccttcccctcccttctcctcttttcccctcccttcccctcccttctttt cctttcccctccectcctttcecctcccctcctctcccctcctcteccctcccttcccct ctcctcctttcccctcccctcacctgtttgactctgctgtgccaggggccagggcagggc tggcccctcactctgcggagtaaatgggtgtgggggccgggcctgtctgggatcagggca gccaggcagggtctcctgcaggagcaggcatagtcccagggagcaggcagctgcctagga aggcagtcaagcagatggggacctcggctgccccaagactggcccggggctggtcetecc tgcgtctggectctgggtgggtggtggtggcttccttgtgacttcatccctccgatcggg caggtggttttgtgcagtgtgtgcctgggaggcgcacggcagcatgatcggtccctgagt gtcacggcagcatcagaggccagtttggcatctggagtagctgccaccgagagaggccca gcegccaggcagctgggagcacaggtgtcggcatcccactgggagcacgggtgaggtgcc tcccttctctgggcagagtttccccagttggtggtgtagacgccaggaacgcggttgtac ggacttcgtgaggatctaacacagcagtgtgtaaaaacagcgccaagcgtgtcctcggtg ggcgctcagaggcggttgtgagcagtgcagatgctgttggcctagttctgacagggtggc ccaggggtctccccgtggcgtggcatggacggtggcagctcctgtggtcatcactgccat ggtccggagcggccctgggctctgcagcaaggcggtgaatgtggagctgagcggtcegaa tcagggtctgggttgctcgttcaactcaggaacttccccagattcctgagttttectcta gccgaggtcaggggcagccaagggaagggtcagccagctcatccagacctcgctctgcaa caaatctccagcctgggttgccatgaggcaccctggggaggactcaggacgaggcccctt gaggctgaacctgagacctaggaaactccaggtgggtcctaacagggcttgtcactgagc gtaggcctggacacggccctgtggtgtctcacecacgggcaccagtccctgttgagcaag gtccacgcagccctttgttctggacggagctgacgctcaggccacagactecgactccat tcttcagaggcttcatcgcctgcacaggaagagaggcctggagataccaggttgtcttgg ggccacagctggcccttggcatggctggggagcagcaaagcagttcattaggaccagggc _tg_accacaccagtgtccatgcccagaggttctgggttctgcectcttgctgtcgtccggt gcaggecacatggccacctgggaaggccegggtcgtcgtcatattccgagtgtgaccaag - '~
agttcaggggcccaggtacctttctgggcccctctcagggtctttggaaaagtccagaat gagctgggctggtggagaattcaggaggtgtggecagtgcccccctgtgctctcagaagc aggggtcactggcgagagggctgggtggcccggcgatcaacctgaaggcattccttacct gcccttggacccggtgagccagtgactggcgtaggctttcaaacctttcaaaccacttct cctggagccccgtgttgtgtgcgtccctcagcccatgcaccccggaaggcacgcctcgca cccagctgtagagccecatgttgtgtgcacccccagcccatgcaccccggaaggcacgcc tcgcaccgtgctcctggtggggcccgtgccaggggggcccaggctcctggggacagtggc ccaggacttgggatgttagaaataaattttgggtgctgcaaaagaaatagcactcgaaca taaatttaattttctcagcaaggcaattttacttctatagaagggtgcgtcttgcagatg gagcaatggcgagagcacacctgaacgagggaggtggaggtctcatcctaacgcagccag tccctgctgctgtgtggttcccctgttggctagggttggactgcacagtctaagctaatt ccgattggctattttaaagagagtagcagtacgagccggagtggcggggtgaatagtttg acgggaaggatggttacagaacaggtgactcaggatgactaagaacagagcaggtgacaa ggatgactaaggtcagagcaggtgaccaggggtgactaaggacagagcaggtgatagagg ctaggcaggggttgtttactgaaactaggggcaaggatatgtaaagtacaaggaagttaa actttagaatgaagaacaaagaatggggatgtaaccatacggatacattgcttctttgga gaggagctcagaattcattatacttaacaatttacaggctaaaacctttgaagaggaatt tattatgttctacac~gagcggtgccgctggcctgtggcttctgcagggacaagtagtggc tgtggccgggaggcgttcggcagctgtgcttcagccccggccccagcttcagctcttcga gttgetggcttetctaaggcctgtcctgaagtggcctggagactgctgagttacttetgg aatctgcaccgtgaaagtgaaacctggaccatgatgtgaggctggtgagagggtgecctc tgccgtcacccccggccttgtagaaaactcattccaatggccctctggttctcactcagg accaaatagtgatggttttttgtttgttttcgttttgttttgttttgttttgttttgttt tgtttttttagacagagtetcgctctgtcgcccaggctggagtgcagtggcgtgatctcg gctcactgcgagctccacctctcgggttcacaccattctcctgcctcagcctcccaagta gctgggactacaggcgcecaccaccacagttggctaattttttgtatatttagtggagat ggggtttcaccatgttagccaggatggtcttgatttcctgacctcgtgatccacccacct cagcctcccaaagtgctgggatgacaggcgtgagccaccgcgccgggcccaatagtgatg tttttactgctctgggcctgatcgcatgcaccgttgtctgtgctgtgacttccgtcgttg tctgtgctgtgacttccgttgttgtctgtgctgtgacttccgttgttgtctgtgttgcga cttctgtgggatattcgttggagaaggagccacacagctgtgtgggacccggcactcett catcaccatcatccagggccacggacaccccctctcacaagtcgctgggatatgaaatta gggaataaatgggaattttcagtgcgatgcagctggcgctaggatcctcctcagtgtgac gtctgagaccttttcccagctggagccctgtcattcattcattcattcatcccatgccag gctgggcggctgccagaggcacaatceggaaccgccccttgetaatgggcggaccagtga aagcaaagcgggctcactgtgcagaccaatgattgacagttccagggtgtgatggacaca ggcggctgccaggaaggagccccttcagaagcagtgggcggggcggggtggggaaggccg tggggaggagtgacttccagatgaggctcacaggactgtacecggagggagggggcagca aggaccctgtgggcagccgggggcacggcacaggctgtggctgtaggtgtgggtggtgcc caggcattgacagaagggagctcactggacggggcagcgtggaggtgagggtcgggtgag ggcccctcgggagcccctggccatgttagttgcacatttcatgactctttaaggagttag tgaggcctgggtgtgacctatttcccgttccaattaaacaggtcattagtccgtgtcgtg etaaagcagatcactcgcaaggaatggaaaacccttgaaataegttttttaaateggtga aagtgagaaactgatgcctctgtgggaaaagaccagactccagggtctgcaccctcagag tgatgagcagcgtctgttaggggtgacctgaggtecctgctttgaaccagettgttgaaa ccggaagccatttctcatcttctgtaagagcctgcagcccctgtcagatgccagccattc cccaggtcttgctgacactgtcattaggattcctatgagggccagtggggagacagctca gtCtCggCCCtgCttCCgaCCCCaCCdCC2.CCCCCaaatgCataCtgctggCCtttCCtg ggtttaattttattttgcagtggtagaggttgttttgctaaaattatttcaaaatctgcc ttgtggaaaaacgcccacgtcagggtgaccatctgtggtaaccgagaattccttggaggc agcgtcttcaccgcctggctaagcggatggcacaagctgccagccagacctctgtctgtc cctgcccagaggccccagctgccccttcctccaggcacctccctgatctctggagtccag gttttgttcccaaggtcctacctttgtatctaaatgctgtgtcctctccccggacgatct cctccaggcactggctctcaggggccagctccccatgggcgatgatgtctctgatacagg aacttatgggtacettgcaagtttgcacagaaagtggagcccgtctgttccttctggggt gtgcgagcggggcctcggggagcaggtgcaggacagggcacaggaggaacaggcacggct ggtggtgtgcagtgaacagcagtggtcacaccaggtggtggctcccgtgggacttttgag gccggcccagccctgagcaggtggggtctgcagaggcctcgtgggttggaggagacttat _. ..._ __. tcagagggagttttggtcttgctagaaattgcatgagatgaaagatgacattttaattet _ atcattgaggcatagtctttccaacacaccccctgaggtgtgagggaggctgtccctata tgatgtggtccccgctccttcaggctggggctcctggccagttcatctttcgtcctgtgt ctgactttctctatcatttctaaaatgactaagacaatttattttgttaaaaaaaaaaaa aaaaaaaggcgttaagatgattctactttgtagagggatcccaagggagcgtctcctctg ggactggccctgtc~cccatcttgttttccctetaaacgacatgtgagttcccaactctt gattttagttctgacaactggagactttattcccatacctttttaaaactttttaaaagg tttaacttcaaggagataccattccttttgtgtatttggttactaaagctgtettgcatc tcaaatgtgatttaagaaatcaagcaaaatgcactggccacgtcctctcagtagggggag gccagcgggcatetcccctcctcgccccttctctggtggtctcactgatgtcceccggec cccagccctccttcctttetttcccttgactttgtectcagactccagggacaacecctg gtgcgagacatcctgttgctgatttacttgttctctcatttgtttctgtgtttgttccat ttctttcgttcattcattcattcattcatactcagctgcggagaccatcagceagtctgc gttcggcctgtgtctgccactggctgcagggcecggggcaaaggtcttcaagtgccctgg gcttcagttccccttcctggagaatgagggtgggagagcacctcccctgggggtttgcga agatgacatgagcccgtgcatcctgggtctggaccgcatctgatacttagcaggtactta gcagcaggtactgagtagacacagtgctccacagcaaagatgtgtggcagaggcgtagtg gatgcgtgatcgagacgcacagtagacacgcaaggatacacggcagagatacgtggtggg tatataatggatacagcgggcgtggtggatttataacagatatgtagcagatatgtgata ggagccaggcatggtaatgacaagtcaggaatgtcacagaggactgtgtcttctgggggt cctggggccttttcacgaggaaggattgeaggtggggctttggaaaaattgtccaatttc catcccctgtctcctttccccggtcaccgetcctacccagtagcaggtggagaaggtgac ttccatactgggggccaggatcaggagcagccacatgccagagcgggtaggcagcccctg gtgcctgcctggccctgccccgacctccacaccagttcagccctgtgtcctgcccaggat ggatgggtgggtaatttattgattcattcatttccagggtctcgtgtgggctttgtgaag cctagtacacgttttttattgcgtttttttttttgtttgttttgttttgttttgtttttg agatgaagtetcactgtgetgeccaggctggagtgcagtggtgcaatcttggctcactgc aagccccgtctcccaagttcacaccattctcctgcctcagcctcccgagtagctgggagt acaggcgcccaccaccacgtccegctaattttttgtatttttagtagagatggggtttca ctgtgttagccggg~.tggtctcgatctcctgacctcgtgatccgcccgccttggcctccc aaagtgctaggattacaggtgtgagccaccgtgcccggccctcgtttttgtttgttttac tttgttatgagtaatgatagatttctagaaacttcgtgtatttttttctccactttattt caactttgtagaaagagatctaaaaatgcaagtctcctcccccaacccccaactctcctg cgtcacggattggttcagaaccaggagacacagggcccagaaacctaggggctggagggg ccttaccctttggactcttgactgtttttatattctggcccctccccccgtctgtctctc tctcaagagacagggtcttgctctgtcgcccaggctggagtacagtggtacaatcacggc tcactgcagctgggctcaagcaagectcecacctcagcctcccaactagctgggacttca ggcgcgcaccaccacgcttggctaattttttatttttagtagagttgggggtcttgattt gttacccaggctggtctggaatgccccaagtgattctcccacttcgcccgcccaaagtac tgggagccaccacgccgggctagactgtggggtttttggggggcaagaattgtactcata tetctgtttccacagtgggtcttacactgtggacaaacagcagctgatgttctcacccgg ecttgttctaagaggactecaaaaagcaagtcgtagccccagtgactgggaaaggcttcc ccgggagageggccgacacagctgccgcagtagtaagggtttatttatcaagactgattt atttatcagttcaagacacagttacacagagtgtgggggatggttcatcagcagctggca cgtccagtggcgcgtgtgcctcgggaaggcctgggagggggacacaggtgctccgcaggg aaagctgcccccaccccagcccaaagaagccctccaagctccatcagtcatgcagtcatg tacttttcctcatcagcacaaaccccgcttccttgaagagaagegtgaggctgggcacgg tggcgcgtgtctgtaggcctagctacgagggaggatcgcttgagcccaggaggtegaggc tgcagggctatgattgcaacactgcactctggcctgggcaacagagaaagagagagagga ctgtctagaagggaaaacagggatagcaaagtagatgggaaggaagggcctctggggcgg cgggtgagtgctggccgctcccctctccacaagctgctgtggtctctgggggetgcacct gaggcggcagtgggaggagaggggtgaagggcaacgcgcccccgtttaaacacctcctgg cctggacgccagctgttcacttgtaatcactggtcaccctgaagagatgggatggacccc tgcccaacatttggctcaggtgtccacacagatgacagcaccgcacgcagacgggaggga gcttctcaccacataatgaggttttctggggagagcaggggaggggggtcttccaggatg gtccagaaaggtcttgagcgcgcctgtaaggagactgtctcggtttccgtggcggctctg gggcaaggcggggtgagcaggggctgaggcttgcagggtttgaactttccccagggccct catcacctcactgggatgtgggcgggaggggagcgggtcgtctcaaacacctccagcagt cgaacatcaaaaagggggtccaactcttggttgcgatttctttggctgaagectggactc ctagccccacgggctgagggaaggttacggctggtggttggatagacgccagtgcttgcc ccagagctgcaggggaagaaggtggcctgaacctcagggcctctgtgtccagttcagggg __ ccagtacagcagcatcggtctgcgaggggtatgtgttctagaggagtgaggggacagaca ggggagccccagaggcatccagtggcgcgaatggtgggaagggccctaagaggggaggct gggaggggacaatcccaggtggcaggggatggccgcgatgaggccctggggtggagccca ggcagggagcatccaggggaagccagtgtgggtggggactgggaggagagagggaggctg ggcctgccctggcgaggggtggtcagaacatcgctcggtgccagacaggcaggacgcagc gggctggcctgcggggctcactgctgccccccggggccgagcacgaaagggagagttgga gggcgcttcctcgccgggtgttgcggtgtgagcggggactggtgagtgtgtgctgtcttc agagagagaagagcagttttcagggtgagtagcctttattcttcacacctcattacacag cacccaggccttttattcaggagggcgcggecggcctcaccccgacagccaccctggctt gttgaccttgatctgtgacagctcccctgtgagttcagacttctcaaggacgcttgcata gccaacattgttgagaacgagtaaccccttatcacagcacacgtctgtcgtgccatgaag caatttcccatccctgtggctttgaaggcataagtcactgcgtcacggccatgctgttcc ttecaaacetgctcgtcaggagacagctcttgcgctgtgtaccggcactgccgcccagca ggtgaccccagcagctggtttgtccctgcctgggggtgagggcctgcagggtgtttgtag acgcaactcttgaaaggccctgaggttggggcttggtcatgagggtgcceggggcccatc cgggagtagaagtaagtgcactaggcatttggccaagggtcacgttaggccttatttatt tattttttgagacagtctcactcttttgcccaggctggagtgcagtggcgtgatctcagc tcactgcaacettcgcctcccgggttcaagcgattctcttgcctcggcctcccgagtagc tgggattacaggcacctgccaccatgcgcagctaatttttgtatttttagtagagacggg gtttcaccatgttggccaggccggtctcaaactcctgacctcaagtggtccacccacctc agcctcccaaagtgctgggattacaggcgtgagctgccactcctggccaggtcttttttc aaataaatgtctaagcaaaatgaatttggggtgaagtagtcacagagctgtcaggaggag cagggtggctgcgtgcccctgggagctgctgtgggtgatgaccaggtgatgccgggaagg tcactttcagacacatagttgtcatcgtcggatgagaattattctcaggtctcaggtggg aggggctgcccaccaggcctggatgaggccccacccccccacacacacatgctgggacca cgagtggcaccccctgaggatgagggggctcctgcgtttgtgccctgtgtgggaggtgcc acctcatttgcatgtggcccttccacgtctcctggccatgccagacaggtcctcaggatt gttgggagatgagggcctcgcccaggacttcgatggggtgtccccccagccccctgtggc tgatggagcagcctgacattttgtggacacaaagccccctagagccagggaaggacaggg ccggacccagagccagggaagggaggtggagctccagccaaggcatccaaacatcaaaag gcagaactgagcggcttggtacttgaaaagtttttattaggaaaaatgccaaactgacag aagtagagagaattacatagtgaggcctcgtgcacaccctgcctggctcctggcaacctg cactccagccgatacctgtgactctcagcaagcccctctagtgggegaggacctccacac gtgtcgccaggccaggegactctcagcaagcccctccagtgggcgaggaectccacacgt gtcaccaggccaggtaactctcagcaagcccctctggtgggcgaggacctccacacgtgt caccaggccaggtaactctcagcaagcccctccagtgggcgaggacctccacacgtgtca ccaggccaggtaactctcagcaagcccctctggtgggcgaggacctccacgtgtgtcacc aggccaggtaactctcagcaagcccctccggtgggcgaggacctccatgcgtgtcaccag gccaggtaactctcagcaagcccctctggtgggcgaggacctccacacgtgtcaccaggc caggtgactcttcagcaggcccctctggtgggcgaggacctccacacgtgtcaccaggce aggegactcttcagcaagcccctccacacgtgtcaccaggccaggtgactctcagcaagc ccctccggtgggegaggacctctgcacgtgtctccagaggccaaagcagaagaaaacgtt agcacaggagtcacttgacttcaccaaacgcagccaggattgcggtttctccggctcggc tgtctcagttgtttaagagagttcatgcttttgagatcaaagttaaaagaaggcctgtgc ctcgcagggcctgctctgcctcccccgtgtttcctcggggttctgcgtctgtgacegggg tgcggagcactggtgtgcagttctctgtctcgtgattcgtgtaacagtgagtgctgcctg caccaacagccggctgccttccgtggctgtgtgggctcctgtgcggaggccgcccctctc cctggccaagcaacactgaggcgggattgcgtcctccctctcctgaggcaggtcctgctc cagacctgcttttttcccgcacgtcacgtgtcctgagacccctcagtggatgcgtcctct ctccttccacggccgcacacactcccgtgcccgttgggctgggctgactgatgcatgtgg gggctccgtcccatctttttcaactacagatggagctgcggtgggaaaacgtgtgcagat acctcccattttacttttgtgctggggcttttttgggatcagttcctagaagtaggggac tgggtgaaaggctgatcaccctcagacaccgaacccctggaggaaacacagggagggagg atgagccctgcgaggtgcaggccttcttttaacactgaccttgggttctcaggactgccg aaatcccctctacccgggctgtgcctctccggcctgtgcctctccggcccttcggcagtg tcgagggagcccccaacacccagcagcatccagggatttcccccagggcagtgtcgggag cccccaacaccccaacagcgtccagggattccccccagggcagtgtcgagggagccccca acaccccggcagtgtccagggattccccccagggcagtgtcgggagccccccaacccegg cagtgtcaagggagcccctggcagtgtcaagggagcccccagacagtgtcaagggagccc _.. ,eccaaccccggcagtgtcaagggagcctgcctccgtggggtgctgccagccttaggcctg ggccagtcggggtggttggatgcctgttctgggggtagagaagtcaggtagcccagggcc cgcactctcaatagaccttcagagaaaaggcatcgaggtaaatgccgcactcgagtaccc gtgtgatctctgggtggggccatgatccttctgggcgctggtccaagcgcgtggtgaggc cgtcctctcctgcagaaccccggcctcttcgcccctgcccgctcacctgttctgtcctgc tcacctcctccaggaagcctgcctggccttctccatgctgatgggcgtggccccttgtcc ctgcagccatgcattgacctccgtggetcctggaggccaggccacgtcctcatcccctct gggtgagtgagaggcacagcctgggtgcgtggggecgtggcggetecgaggcgccaccgc tgtgtcctctcatgagtgggtgccgtccaggtctgtcctgggctggctgcgaggaggagg ttggcctcgcgcggccatgtgcgtgacagtggagacatcgccagcctcctgcttgcacag ctgacggcagcccctctctctccagccatgtccccaggactcttgagtagttggectggt ggccgtgggagaagcaggccccgagtccccagggctgtgagcgaggctgtctgatgtgct ccctggtcaccaccccctgcctgtccgtettgcctgggcagatggaggtggatgaacttc ctgcggccgctgtaacagtggccgccactggggggcttaaagcaacacgcatttgttagc tcagcggtctggagggtgcgagtgcagatggagctcactgggccaaatttagtcaaggca ccagctgggtgggttctttctgggggctccagggagaccccgtttcccgccttctccggc gtctgaagccgcctgccccttggtgcagccctgagtcaccccagcctctgcctccgtctc acgtcaccgcctctgatacagccgcccccccatccctcttgtgaggaccccgcaatgacg tgggcccacccagatcatccaggaacatctccccatecccacgtccttcacttcatcgtc tgcaaagtcccgtatgccacggaaggtgacacagtcttgggtcccgggacttgcatgtgg ggctgtctgggttttgcacagctgaccatgggtgcttccggatgcttggcattggaggtt tctgtcctctgctggaaggattcctggagtgagggcagcagagggcacccagatggaggc actgccggacgcgcaggggcgatggtcggggggcacctgggagccaccttcccttgtctc tggggggtgacccttgaccttggtggcctcagttttctcatctgtaaagtggtgcacacg atacctgctccgtcctcctcactgaattgtcctgagatcaggtgtggtcgtgaatattaa acatgtggattgcaaccctagacagagctcccttggacggttgagcagatgcagccaggt gtgggtccggctgtgggcggagggggtcacacggggccgagtggcttcagcgagagtcca taggacatggagagtcccggccgtggtgaggacacggggttgcggcagctcacgcccact gcagtgtccggaaggcggtgctaggtccacctcatttacggggtcgggctctcattctcc ccattgtacagcccagcctgtagaggcaggtgaggtccaggccatgggcctgtgggccgt gccacgtegctcagattttgtggtgtcggtggtgggagccgccggggaaagccgtcatcc tggagccgggcgagagagggecagggcagtggggtggactccagaaatgtccagtagcag aattgccagacctggccattggctggggtgttgagggagacgtctccagggatgtecagt gtctcccagtctgggcaagcggaggagccggccagcatgggccatttcatcggggccctc cctgggggcagccaaggacctaaaaccaatgggtcccaaccaagaggatcccagaggtga gacacagaacggccagggetgaatecggggccctccctgggggcagccaaggaeetaaaa ccaatgggtcccaaccaagaggateccagaggtgagacacagaacggceagggctgaatc cggggccetccctgggggcagccaaggacctaaaaccaatgggtcccaaccaagaggatc ccagaggtgagaaacagaacggccagggctgaatctgcctecagcgggggccccgggcgt gatcagagcaggcaggacctttcttccctctctgcagctccggcactggcttcctccgtt caggcttcatccccggtcagggggctcctggtcecgtggcagceccgtggctcctgggtc gcagcttcatgggggaaacagagactcctctggtaccagggteccctgaatctccggagt cccccaagtccattgagtccactgggcccgaagagggaaacagagactcctctggtacga aggteccccaagtccctggagtcccctgagtccactgggccctcgacacccttgggtcac ttgtccaccctcacaccatcgctggcccagggaatgggggtttggatcggccttggtgac tgtgggcctctgcctgaaaccctgtgagtgtgggtggggtgggctgggtcctgagagagc tgggagcagcggagtgaagggggctggggtggggctggtgacagtggagtccctgtgggg ggcagggctggtggacagtagagtccctgtaggggctggtgacagtggactctgtggggc cagggtggggetggtggacggtgtagttcctgagagacegagccggaaggtgagggactg gaagcttgcacacgtccctgcggccttcccctcgggtgcgaggcctgccatcctgagetc ccccaccctaccccgtgcccgccctgagggcgggacccaggccagttcacacagcatggc gaggtaagggctcaggatggaaggcaggaggaaagttgggcctgctgcacccatgggtat tgcggcagggaaggcgaggaggagccgaggtgggtgctgggagctgtggggctggctgtg cgtgttgggcctaactcgggctgagctgaggttactgagecctcaggagggtgctgtggg aaaagaaagaggcagagaaggtgtctttggaccacttaggggacggggagggaaccccac ggcaactgtgaaggtetggggcacagccagggagggtcccaggttgacagggacaggcgg ggtgggggtgcaacatggaggcctggggctgagcctccgagaagtgatgggcaggatgag ggggccagaggggatcacgcaacaaggggtgcaccttggtggtctgggtgtetccagaga agctggttgtcaggactcaagaggcggacagggaggggctggggttagggaagagtgtgt ggcagggggaggaagggagcctgcttgccgggtcacctggcattgggagctgtcccctgc ctgctgcgc.cccgcctgccattgttggagttctccagtctgggctggtctggatgaggaa .__.
etggcggggctgctgccggcctggactcaggaccctcaccctccagcccgcaccctegac tCCCCaCCagCCagaCCCtCtgtCCtggtgtggaCagCa.CCCaCatCCtggCtCCa.CCCt tgtttcttgccetttgacctacagcctcaggacgtgcaggagggaggtacgtaggcactt gtgggtccggcctcctgaccgaccgtccatccaccaccaggcttctggatgttcacccat gtgggagagacgggtgtcggggaagggaccacagcttcctttcagaagacccgggaaggg cagtgccgtgtgccagcetcccagttggcaccttcctttcaccttagtcgtcttcgaggc gatgtttcctcgggacaagtcattttcatgaatctgctgtaaaacgtctcccaaactcca agtgtttcccaaactgagtgaaaatcgctgcagaatgtggtttccagcagagcttttccc ctctccttccttcacctctgcctgggttacagggtgcgggttccaggagtctgcctagaa ggcaaaaaacaggctttgcttagaatccectaaattgctcataaaacacagtgtttgacg tttatgtgtagacatgatcettatgtgggttaagctgaggcecctgceccagtgacacag aggcctcaaacggcacagtgcaccttctgtccgaagcagccggcgaggcggcccgcgaac ctctgacgtgctccattg~caatgaggatgaacgagcctcaggcggagggtcagcctggaa cccctgccccgtgaacaccagccagcttcatgctgaggacccctcagtccaacccagagg cccatgctgaggtcccggcatgggggactgtggggtgcagccgccgcttggageggaggt gaatgggaccccacacgtttcctcctccttctctggatgcctgtaatcatcacagtactc aaaaaaggaagaagaaaaaggtccttgaaacttgctggagttgcagttccgtttttttgt ttgtttggttggttggttggttttttttttttttggagacagagtcttgctcttgtcgcc caggctggagtgcagtggcgtgatctcggctcactgtaacctccacetcctgggttcaag ggattttcctgcctcagcctcccaaatagctgggactacaggagctcgccaccatgtctg gctattttttttctatatttggtagaggcggggtttcaccgtgttggccaggctggtctc gaactcctgacctcaggcgatccgcctgccttggcctcccaaagtgctgggattacaggc ttgagccactgcgcccggccccattttctttacatttgtgacttacagtcatcagctgaa ggaaagacagtggcttggctagggcctgcccactgctggccgaggctggccgggtcaccc aggtgcctgcctetcctgctctggagccgggcactgcctgagggcctgcagcaccagtca gggccccgggggatccctccagggtctcagttctgactagcgagtacctcgattcatgag tatgttttttaatgtaaggttttaacgtaaggtttaaaaaggcagccgccccgtttcctc cccactggtctcgccttcagcagtgatttgtggtgactgtgacgttctcttcggtgggct gcctgtggatcgccaagtatgtgctcctgctgettetacctgatgtctccccatcttggg ctttgaggggggctcatccggggcattcatattttctgcccgagttcgctcctgacccag ggcaggtggaagccagcaggtgaggaccagggtgtcagccagaaactcggaagtggcaca gaggcagcatccgatagcccctttgtcagaggcgaccagggccttgagtgagetgggatg gacttctcttatcctgacatcctggaagggggtgcagcctgcctgtctgtgtcccagttg agttggcaacattttttgtctttcctcatgatgcacgaagtagtggtatctctgagagcc aatggcagcetagctgccgtggagaatgctggggggtgggtgagagttggggcacagagg actcatggggcagaggctgtggtccagtccttgtgggggtgactccagggatggcaggtg ggtggtgtggccaaggaggagggaggtcaaggcactggtgttggggcagggagaagggac cgcagtgcccatgtgtttgagggaggggagatgatggtgtgggagtgtagagagggcggg ggcccagcceacagcatccatgccctggggattgggtgccaccggtcaagggctccacgg ggctggctctgggggagggagagcgggcgccatgttgtgtgtgtggtgcgtgtggcgcgt gggtgagggtatggecggctgcgtaagtttgtggaagcgttcggaatgctcaggagataa aaacagcagagggctgcacccccccaccctcccaccccagcttttctccaggaggacgct ccgtcgtggcctgggaggacgtggaaggagggaccccggatgcagggcaggttcgtcttg tgtgttgagaacgtgctctccagggatctgtgttaatacaggtagcccaagcacagtgtc caatgagggaaggaacatttgaaacagaagagatgacttattttgttggacaaaaaagga atatggtggacattaattcttagaagaggttttatttgaaacaagtcacaaaaataatca aacagcaggttgactttggagttcagctcacaaaagttaagcttacagagcaaataaaat aagctgaagaaaaagataagatgactgggcgcagtggctcacgcctgtaatcccagcact ttgggaggccgaggcgggtagatcacgaggtcaggagtttgagaccatcctggctaacac ggtgaaatccagtctctactaaaaatacaaaaattagccgagtgtggtggtggacacctg tagtcccagctgctcgggaggctgaggcaggagaatcgcttgaacccgggaggtggaggt ggcagtgggccgagatcgtgccactgcactccagcctggtgacagagcgagactccgtct caaaaaaaaaagaaaaagaaaaagaaaaagctaagatgcagcaggtggagccgcctgccg ttgggtttcagcttttcttatggaaagaatgttacggcctgggtgcctccattctctgat ttctttttctttcttgactttttaaaattgaaacaaaactccctaaaacatgaaatctga agcgttcaactccacgagtttttacaaagcaaactgcaccgcgtcacatagctgatccgt gtgtagcttgtcctctggacgcggggccacccccacaccccgaggtgaccccaggcgtaa cctacccgtccccggccttggtgcctgcagatagttttgcttgtttcgagcttttgtctt gggatccggggccatccaccctgggtgtggccgctcagtcgggcccctgtgtggggcttt cccgtggtgtggggtgcggttctgccgtgtccgtccccactgcggggc-tgctctgctggc tgaattctccacgtcttatgtatccaccctcatcttgcgaggcaccggggtcccggcttt tggccacagacatccgagcgccttctgttgcccgtggcgcatctttcatgtgggcacacc caggagtggagtttccgggaaacagacgtttccctcgcgtggccgcaccaggtcgcactc tgcactgtgtttctgcctccagttatgtggggttttctgcacccacagccactctggcgc cagctgggtgtcctgtgtttccattcagctctgacatcaattacctgacgttagcgcaga ccctgcagatgaagggctcattcccacaagcctgcccctacttgagagccagctgcaagt gccaggtgacaacctggattctgaccaactggctgtgaatcgggggtgtccgtgacccct tcctgaggctcgggtgggctagaatagctcccggaactcaggaaaacactttgcttagtg tacccgtttattagaaaggacagccacacggaggagctgcacgggaggctgaggtatggg gggtgcagagcttccgtgccctctccaggcacgccaccctccagcaccttggtatattca ccaactcggacactctccagaccatgtcattgagggctttttgtggaggcttegtgacag gcacggttgattcaacagccagecactgctgattacctcagtctctcctgtctcetctet ggaccgtgggctgtgggacggaaagttccaacccgctaggcattccttggtcctgctgaa gaccagccgcatcetggagctgtcccggctcccggctccccgtcatctcattagcatgca aaaagacactcttaccgcactccaggattcetagggtcagaggggctgcgcgctgggaaa ctgagacaaaggctgaatctgtgttgatggcacagtcactctgggtcgtgtgggaattcc cgatgcacctccttccagcacatggactgtcagagccctgcgttgtcgecagcacagcag atctgaaaggcactaggctgtggcctcgcgacggctgaggtgagctgcttctccgagget cccgggttattggggaccctccttttaaaggtgcctgttccagtcttttgccccatttca aaattgggctgtcaaagaacaatgtcattggggggtccgtcttttttgttggttcctggg ggctgtgtgtgttttagagacaagtgctttgattttttgtgttgcaaacagcttctgtca ctccgcggctcgccttccactccatggatggtgtcttctgatgaacagaaagtaaaagct tactttataattagggcttttgcgtcctggctgtgtgtggggcctctttctggactgatc tgtcccctttgttttttgcccccatgtcgtactgttctgatttettctgctttataatca ccattggtaacttgtgttatgagtctccaatttggggtttttagttttcaaggttatctt ggttattggctttttacatttccatacacatgggcttgttaataagccatttacagttgg cttatttgctttcaaaatctccataagacatttggattgcatttggatttcttgatcagt atgggagattagcatctttacaatactgaggtttccaatccgtgaacatatctttaggcc tttgattggggtttttttggcaggggagttgcggggggcagacaggacctcactcttgcc caggctggagtgcagtggcatgatcatggctcactgcagccttgacctcctgggctcaag caatcctcccacctcagcctcccaagtagctgggactacaggtgtgcaccaccatgccca gctattttggcatttttttgtagagacagggtctccctatgttgcccaggctggtcttga actcctgggctcaagtggtecttctgcetcagcctcctaaggtgctgggattacagatgc aagccactgcacccggccttaaattctttcaataatattttgtagtcttgtgtgtagcgg tcatccacattttttgttcaaatgattecctggtatttcagtgcttatgctgttttaagc cgtattacttttacagtttttttttttttatctttttgtttatagcaatgtgtaaagaag tgtgattaactcatttgtcttggcctctcctggtccccgtagtttgtctgtggttgetcc ggaacctctctgtgcgctgccattttgtcagtgaceggctgtttgtttctgcctttcett cagatgttgccttgttaccetggcactgttgatccttccaaaacagtatgggacagaagt ggtgacagccacatcctctcgtgcctgatttcagggaaaagctttaagaattccaccatt aagggtgctgtttgcggaaatactgtttttccttcgtaaatccccaccaacaaattaaag aggttctattttattcctagttgaaagttgttaatatgaatggtgctgaattttttcaga tgctttttttccttcatctattgatgtgacagaacttttctcctttattctgttcatacg atgaattctatggattggctcttaatggtagaccgatggcattcctgtagtgtgcctcgt ttggttgtgatgagttcgcetttttatattttgcttgattcagtttgctattattttgtt tgttgtttttgcaactgtatttatgagagagattagcctattatttcttttttttttttt tttggagtctcactctgtcacccaggctggagtggagttcagtggcccgatctgggcgca ctgcaacctccgcctecctggttcaagegattctcctgcctgagcctcctgagtagttgg gattacaggtgtgtgccaccacgcctggttaatttttgtatttttagtagagacagggtt tcaccatgttggccaagctggtcttgaacccctgaccttaggtgatccgcccgccttggc ctcccaaagtgctgggattacaggtgtgagccaccatgcctggccatatcttccttttga ttgatgcttttatcatcatgaaatgtttttgtttttttttttttgagacagagtgtcgct ctgtcccccaggctggagtgcagtggcaccatctccactcactgcaagctctgcctcctg ggttcacgccattctcctgcctcagcctcctgagtagetgggactacaggtgcctgccac cgcgcctagctaattttttatatttttagtagagacgaggtttcaccgtgttagccagga tggtctcgatctcctgacctcctgatccgcctgcttcggcctcccaaagtgctgggatta caggcgtgagccactgtgcccggccaaatgttgctctttagatgaaaatattattgtcat taacatctgatctgtatgatgttagtgtgaccacaccagctctgtgtgtgtgtgtgtgtg tgtgtgtgtgtgtgtgtgtgtgtgagatgaggggagggagggaaggggacttagtgttta tatgctctattttttcatcctttcactttcttttctgtatattttggaaatgactcttaa aagcagaagttagttatttttaatccagtctgaaaatggctgtgttttaaatgaaagatt tagtccgtttacatttaatgtcattctgatgtgttacattgtagctttgtcatcttgcta tgggtccttatttgtccggtctgttctttgttttgtccctctttcttgccttcttttggt ttaatcagatgtttttattccactttcctccctttattattatagctttgttaagtaata cttctcttaatgttattttaatggctaccttagaaattatgagtcacatecttggaacgt agcataaactacttttaccattttcttcaaaaccttataacagtttaattcttatttttt ccttttttttttttttttttgagatggagtgtcactcttgttgcecaggctagagtgcaa gggcgcgattttggctcactgcaacctccacctcctgggttcaagtgattctgctgcctc agcctcctgagtagctgggattacaggtgcccaccaccatgcccaactattttttgtatt tttagtagaggcagggtttcaccatattgaccaggctggtatcgaattcctggcctcaag tgatctgtctgccttggcctcccaaagtgctgggtttacaggcatgagccactgtgcctg gcctaattattcttctttccttattgttagtttgtgctattattttatcagtctttgtgc tgttattatcatgcctgtaaattctacgtgtatttcagacccacaaaccaagtgttgtct tagacagtggtccttcagatttacccccaggttacccttctagtcttcctgcaggacggc gcttacatggagaccagcttccttctgcctgaagtagtccctttagtattcctttcagca cagacttgtaattaattctttttatttcttttcttttcttttttttttttttgagatgga tttttgctcttgttgcccaggctggagtgcagtggtgtgattttggctcactgcagcctc caccteccaggttcaagcgattetcctggctcagcctcctgaggagctaggattgcaggt gtgcgccaccacgcccagttgttttttgtttgtgtgggaaatgtctttggcattctttct ggagggtgttcteca.ctctgtgtggagttctaggcaggtagggggtttcccccaacaggt ttttgtgttggcttggagtgtttgtcatttctgtggtgagggcgccttccagcctcactg ccacccctggaaggcaacatctcttttctctgactcctgttaaaagtgttttcatcacaa cagcagccttgtgaaggacagaggaatcgagaatttctcetaattgagattggtagagct tcttgaatcagggacatgatagcttttgtctcttttggaaaatatcagcccttgactttt cgtttttttttttttttttttttttttttttgagtctcgctcttgttgcccaggctggag tgcaatggcgcgatctcgactcactgcaatctccacctccccggttcaagtgattctcct gcctcagcgtcccgagtagctgggattacaggcacttgccaccatgaccggctaattttt tttgcatttataggagagacagggtttcaccatgttgaccaggctggtctggaactcctg atcatacatccaccttggcctcccaaagtgctgggattacaggtgtgagccaccgtgccc ggccagcccttggcttttcaaatagcatcctgttctctctcccctgggacccccacactt cacacctgtgtgtctaatgtgctcttttttctgggtttcttctgegttggttttttcccg ctttgtgcttcaatgtggatttttttctactgttatctcttatttcacccaatctactct taaatctaccctttaaattattaatttcagtcacttcattttttacttttagaatttcca tttgattctttttttttttttttttgcccaggatggcaatggcacgctctcggctcactg caacctccgcctcccaggttcaagcaatattcctgccccagcctcccaagcagctgggat tacagggtcacactaccacgccccactaatttttatgtttttattagagacggggttttg ccatgttggccaggctggtctcgaactcctgaccttgggtgatccgtttgcctcagcctc ccaaagtgttgggattacaggcgtgagccactgcgcctggcatcgtagttctctcttctg gggtgggaatgtetattctgtgtccttctcacgtgcaaaatactgtcattacatcccaat ggccccagaacccttaactcctcccagtgtggcgggggcagtcttgtctgaacaaggcat gggggagcctggaggcccattcctcctgaggccaagttcctccctggctgtgggccagca taagcgaacaaggcgtgtacttccggaatgetatggactgagtgtgtgtctccccagaat ccatatgttgaagccctaaccctccagtgtgatggtgtttggagacgaagcctttgacag gtagttagagtcatggcggtagttagttagagtcatggcggtagttagttagggtcacgg tggtagttaggatcatggtggtacttaaggtcatggcagtagttagggttatatcagtag ttagggctatggctgtagttagggtgatggtggtagttaaggtcacagcagtaattaggg tcatggtggtggttagggtcacagtggtagttagggtcacggtggtggttagggtcgtgg tggtggttagggtcacggtggtggttagggtcacggtggtagttagggtcacggcggtac ttagggtcacggcggtggttagggtcacggcggtggttagggtcacggtggtggttaggg tcacggcggtggttagggtcacggtggtggttagggtcgtggtagttaggttcatggtgg tggttagggtcgtggtggttagggtcacggtggtggttagggtcacggtggtagttaggg tcacggctgtagttagcgtcatggtggtggttagggtcacggcggtggttagggtcacgg tggtggttagggtcacggcggtggttagggtcacggtggtggttagggtcgtggtagtta ggttcatggtggtggtta.gggtcgtggtggttagggtcacggtggtagttagggtcgtgg tggttagggtcatggtggtggttagggtcacggtggtggttagggtcgtggtggttaggg tcgtggtggttagggtcgtggtggttagggttgtggtggttagggtggtggtggttaggg tcgtggcygtggttagggtcgtggcggtggttagggttgtggtggttagggtcacggtgg tggttagggtcacggtggtggttagggtcacggtggtagggtcgtggtggttagggtcgt ggcggtggttagggtcgtggcggtggttagggttgtggtggttagggtcacggtggtggt _._ .._... . tagggtcacggtggtggttagggtcacggtggtagggtcgtggtggttagggtcgtggcg gtggttagggtcgtggcggtggttagggttgtggtggttagggtcacggtggtagttagg gtcacggtggtggttagggtcatggtggtggttagggtcacggtggtggttagggtcgtg gtggttagggttgtggtggttagggtcgtggcggtggttagggtcacggtggtggttagg gttgtggtggttagggttgtggtggttagggtcgtggcggtggttagggttgtggtggtt agggttgtggtggttagggttgtggtggttagggtcgtggtggttagggtcgtggcggtg gttagggttgtggtggttagggttgtggtggttagggtcgtggcggtggttagggtcgtg gcggtggttagggtcgtggcggtggttagggttgtggtggttagggttgtggtggttagg gtcacggtggtggttagggtcacggtggtagttagggtcacggtggtggttagggtcacg gcggtggttagggtcacggtggtagttagggtcatggtggtggttagggtcacggtggta gggtcgtggtggttagggtcgtggcggtggttaggttcatggtggtggttagggtegtgg tggttagggtcacggtggtagttagggtcacggtggtggttagggtcacggtggtggtta gggtcacggtggtagttagggtcacggtggtggttagggtcacggcggtggttagggtca cggtggtagttagggtcacggtggtggttagggtcacggtggtagggtcgtggtggttag ggtcgtggcggtggttaggttcatggtggtggttagggtcgtggtggttagggtcacggt ggtagttagggtcacggtggtggttagggtcatggtggtggttagggtcacggtggtggt tagggtcgtggtggttagggttgtggtggttagggtcgtggcggtggttagggtcacggt ggtggttagggttgtggtggttagggtcgtggeggtggttagggttgtggtggttagggt tgtggtggttagggttgtggtggttagggtcgtggcggtggttagggtcgtggcggtggt tagggttgtggtggttagggttgtggtggttagggtcacggtggtagttagggtcacggt ggtagttagggtcacggtggtggttagggtcacggcggtggttagggtcacggtggtagt tagggtcacggtggtggttagggtcacggcggtggttagggtcacggtggtagttagggt ggtggtggttagggtcacggtggtggttagggtcacggtggtagttagggtcacggtggt ggttagggtcgtggcggtggttagggttgtggtggttagggtcacggcggtggttagggt cacggtggtggttagggttgtggtggttagggtcacggtggcggttagggtcacggcggc ggttagggtcacggcggcggttagggtcacggcggtggttagggtcacggcggtggttag ggtcacggcggtggttagggtcacggcggtggttagggtcgtggtggttagggtcacggt ggcggttagggtcacggcggcggttagggtcacggcggcggttagggtcacggcggcggt tagggtcacggcggcggttagggtcacggcgacggttagggtcacggcggtggttagggt cacggtggtggttagggtcacggcggtggttagggtcacggcggtggttagggtcacggc tgtagttagggtcacggctgtagttagcgtcacggtggtggttagggtcacggtggtggt tagggtcatggcggtagttagggtcacggctgtagttagcgtcacggtggtagttagggt cacggtggtggttagggtcacggtggtggttagggtcacggcggtggttagggtcacggc ggcggttagggtcacggcggtggttagggtcacggtggtggttagggtcacagggtagaa cccttgtggtgggatttgtgccctttataggatgagaggatgagacacaagagaggttgt gctgcgcctgtgctctctgctccacatgagaacatggtgagcatgaggccgccagcaagc aaggagataccccgccctgcaggttccgtcatcctgactccagcctcggaaacatgagaa agtcaatgcctgtcacttaagccgcccagtctgtggtattttgctgtggtggctgagccg acggagacagttccataggtcttgattgtcctggtggccctgaaccccagtttttgtctc cagtgagatgcctggcccggctttctgtgtgacctccgaagggtcagcagacgecgtgca tgtgcagggcttgggtggcgcatctctctggcaacaccttctcttctgacgcacttgtct ggtctcggatgcctccaacgcggtttttacttattttccagctttcgtcgattgttcgtg ggaggagggttagactcctcgcgtggcgtccctggccacatcctcagcgctgtgtcccet cgcagctcagttcctggttctgagttattgtgactcagccgcacgtcctcccaggggcct tgccagcctggctctgtgccgggcgctgggcaatctctgcetccagcctgggcetttggg tctgtttgagggtgggggacacggagctcagcagtgaggaactcggagcagcttcttgtt gttggtgttgatgtgttttgtttgttttagtgaatccagaaaaaaaatttcttacataga aaggagcggtatttggtatgaatttatttgcaactgactgcttggaagttggcgtacatc tttccacggaaactatgaaaatactggtcagcctctcagtcatttcataaaatcttgatt ttgtattacaacaaattaggatattttcagtagaactgattgtaaggccagactgttgga atgtaattccttcccaaacatctctcaggggcactttcctgaacggetgctgacagcagc atttgaggacggtggggcggaggacatcctggggggcctggcttcttgggaactggaggc tttggcccttgtcccacccctgctcccctgaggagggaggcgtggggccctgggctggct gcaagacgtggagtgactgtgggtccccgtggcccctgacatgctcccagggaacccaag aaaagactgagaccctgtggtgcctcccgctttccatccgcattccatggcaggtgagtc tgattattcgaaggaggctggagtgtgggcggagggcagcgccaggttteccaatcagat ttgctcagggtccctccagcagtccatgccgcagaggctgtcccttgggggcccacgcat cctagccacggcctectcacgtccatgcggggatttgcgccetggaaggagccgcccggc tgCCtCtCgCCaaCatgCagC3CttCCCttCCtttCCatggagCa.CggttCCtgtCCCgg gggtccatattggccactgtgggagagagtcgggcagctgaattcccgcaggtgggaatg _ __.... __ccagggcccgaggatgttgcccctgtcctgaaggctgtcgcccgatcgctctatccaagg __ ctgccctggggcagcgtcacctgggggtcctgcgggggcttctcagcacagcatccagca ctgccacctagtgtgttcccgtcacgtctcctccccccgcctgcaccaggcaccagagac ccggatgccaaggcctgtcagcttcctcaatgggaaacttttcttcagtgaacaaagctc tgttttatagactttttaaattttcagctcaaaaaccaaagtctgccagtgttggtggcc ttggagggctggtctgctgacctgggctgcaggggctgcccggctggggtcgtggtcggg gcaggtgccgcccacaggttgtttggctgcaggtgatgggcaggtcccccatcacgtgtc cagaggtgggtgctgctggtgggtaatccagctcattacctgtctccccccagccgcctt gggctggggaccctgccccgccgaccctgccatgcccacccccctccagcctgattgcgt gtctcagtcacatgaccgccctgggcccgtgatgtcactgggaaatgccctcatttgatt ggcttagaccccagatgaacaagcccaaggtcttggggcatcagagccacccatgagggc agctggatgcagcggecacagcctgtggttggggaatggcattgcgcagctccaccacga ggggacctgaggcttggactgtgagactggcccaggctcgccacttgcccctcacccggg gttgccttcccgagggccgcggacacctgagcagtccccatgccactgcattgtggcagg gacacggccgcccatccctcctgggtcccttatccacctgcctgtcccttcgtatcactg acaccctgatacccattgtgctgcgccgtgtggcccggtgcccacagggccgggttctgc ctgttcctgggggtccgtgtgtcccacgtgcctagacgtgagaggacggaagtcggcaga gettggctccctgttcgcccgactggcgectcggctgtgcctcttctgtctctcgagctc ttctgtgccgtgtggttgcactaagcagctgtggggaagggggaggttgttgcctcagtg ggagcctgggctgtggctgccagtccccaaaacagaccctgcgccccgggcaaccatctg cttcccgecacagtggtgcccaaaaccttttccaagtcgtcttctgtgactttagtgtta ttcttcagtcacctttaaaagcatagcatgttttcaatcacatgttcagctgggaaatag atctgtggttagaaacgggaagtttgagttgcaggcttgcgatecgggcaggtccctcag atggaggggctgcacctccactgccccccccaccgccgcccctgccccacggccacccca gatcctcagacgcccctccetgtgccttetcaccctctggtcctggctgggcccgtcccg CCCCaCgtCCCgCCtCCC3CtgCCCtCagCCtCtggaaCggtgCCtgCatggCtggCa.Ct atccagcgcagaagcraatgaaggacttctgttcagacagctctgctgggagcgttetggc ctgaaatgcagtgggagctctggtgcaggtgtagccgaggctcaggggctccacaccagg caaataggcgaacggcgtctcccgcggctcccggtggctttttaggactctgcgttcgtg ttctccattgtccctggcagcccctggccagggtggcccagtgcccactatagagggtgc aggtcagtttgtggaccaatggccaaccaggctgagtcaggtgaggtggggagtcccacc ccaaaccccaaactccagtgtetgggccacgggcagccctgggacaccttagctctggac acgaatttgcggtcattgctgttcttgtgtctctatttgcctaggacatgctggcagcta actgggtgctggggaagcctggagaggaagccaggtggccccaggetcctggagctcaga atctagtggaaatcgctgcccagggaagaagctccggagtctagaggtggcagcacccat tttacctgcaccctcagtgacagctgcaccctggcttetggggacetctgggcccaaggg cacctcactgtctccttgtectcctggtcactgacctgggccaccatagaaggcacctgg ctatctgcatgtggcttgaccactgccttgcacccatccgggccccgcagggccgtcctg tggcactgetttgggctgtgctggtcaccctgtgtagcggggccatgtccagtgaacagg agaggcctcaagtgccccctgacetgctgccagggactcggcccctccctcaccgccacc gcacccaagggctgtcgcctgtcccagcctgctgetecgagtttagtgttttaaaacgtg ttttctacgtcttgtcagagtgctcaaggcgcgagattgccatggaaactgagctcctta gaattcctgtggccgtcctaattatagaatctcaaagacacgcacagagctccttgaggt tgtcggagttaaggctgaaagaggaggagcggcccctgtgatccccacaattttgttccc tgcttgcttcagcagagectggcacccagggaggtggcaggatgggtccecaatgggcac gtgacatcgagccagctctgactccaaagcctgacccgtgtggctgcaccgtecactgtg cgctgtccactgcaggagaccccaggctgtgtccacacgtacccccggaaggacctcetg ctaacctgggcttgactttgagaccctgttccacagaggtagccgggggactcgcggtgc caggcccacagcctc.ctcgccggtagtatctgggggccaggggccgtttccagagcacac tccccagaagggctcccttctccttttcacagcgctgtctgtcgcttaggtcagaaatag gcccatcgctttccaagcagaaacccaaacactgaaaattcgactgtgacttttgagggg tggggaccgccaggtccccccaacatccctgcctgcgggcccagaaaggcagagtggctg ccggcccgcgtgtccaggccccttacactgagggaaccttctagtcaattgcctgaagtt cgaaggtttggggggtttttgtggttgcttccgtttgttttggcagttgcagaatccccc gaaaaggtgggaatgtggatttttcaaggcaggtgetcctttgattcagaagctaaggag gccetaagtgcagtctcaccttgagaaaaatatcaggccagtcctaacggaggggcgtcc tgcagacacccagcctgcactcagaactgtcacggtcagaaagcacggtcagaaagtctg agaaagtcacggtgcagcagggcccgagaggcaagacggtgacacgtgggctcctggaag aggcaggatggtgacacgtgggctccaggacaggaccctggggeggacgcagacagtggg tgaaaaccaaggaaaggtctgaatatcgcttaaggtagccatggatcctgtctcattaat tgtaacagtgtagcaggcgggtggaagatgagagctgtggggagccaggcagggggggtc__ tctgggaactctccaatttaaagctgttcttaaaaatagtctattaaaaaagacagttga gggcggccctgccta.cagctggagttgaggttctagcaccaggcttcctctcagcctcca taggcgagtagggaccaggcagggccttggccacagggaggcttctggttaccaggttct ccacagcctttgcagtttccctgtgaatctgaaattacccccaaataaaaaggatgggtt tttttgtttgtttgttttgttttgtttttgagacagggtctggctttgttgcccaggctg gaatacagtggtgtgatctctgctcagtgcagcctccacctgccaggctcaggtgatcct cccacctcagcctcccgagtagetgggactataggtgcacgccaccacactcggctcatt ttttatattttttttatagagacggggtctcaccatattgcctaggctggattcaaattc ctgggctcaagtgatccacctgcctcgacctaccgaggtagtggggttacaagcatgagc cgccacgcctggccaaaaggtgtatttgttaagtacaggctgccctgctgtccgttatcc cttataactcacctggtccctgctttccagctggggactggcatggaccccatggggctt cccccatttcactg~.ggcaagacccagatgctgggggtattgggtgtcctgcccaaccag ggtccccagggccaggggctcctggcgtgccttcccgtgggactcegcatggggggctgg gagggcgaggaaaatgggaaacatgatgcctgcccaaaactcccacctcggagaccctgt gccagggttttccagagagaccaaaccaatagggtgtgtgtatagaaagatctattgtaa ggaactggcttgttcatagagacttatgaagcccaaaatctacagggggcccagcaggct ggagacctaggaggagccacagccgcagcactgctgcttagggagctcagcctttgctct gtggaggcctttttctgcttgggtgaggcccacctgcattgtggtgggcagtctgcttcc cccaaagtcagctgatttaaatgtttatctcatccatactcaccctcatggaaacatcca ggataacatttgaccagccgtctgggcaccatggcecagccgcgtggacacatacagtga accattgcaggcccttccttggcacttggcatecacgcatatccccttaagccacactca gtctccacacagcagtactcccgcctgacacactcggtctccacacacagcagtactccc gcctgacacagttcgaccctcccgcaagcagtgccagcacacttggccttcccagaagag ggccaccatcatgggctcggaccttccagctggactgcagtggggtggggcgtggcctcg cctctgtggtctttgggtcacttgaatccccgcctctcactcattttcctttggtatttg caaatttgtccccgtggcgcctggagctgactgccgggtgccacatgtgtcctgcctcaa gccaagetccaggcggcacccgtgagcaggcagggatgccagtggtttctcacctgggag tttctttgcaggctcagagctctttgttcctttttaaaaatctgatttgaaggccgggca cagtggctcacacctgtaatctcagcactttgggaggccgaagtgggcatatcgcctgag gtcaggcgttggagaccagcctgggcaacacaggttggggcaactcccttccctaataaa agttcaaaaccaacccttaaagtttaaaaagtgagatgggatatttgaaggaggcaggtc tgagggaaatgcttgaaattatcctctctgtccctgtgctgccaggtcatttagttccat tgttattcaacataccatttgacacatgctaggagcgcaggactcggcaatataaagcgt ggtaatcgatggacactgcccecggcagccagccaggggcaggacttaagccccacccaa ctgcaggctgtcccccgcegctgetagcctgaagttggattggttactgctgcggcctga aattggattggttatttgcttactggaacatttttgtcacatgactgtgtattctaaaac aagatgttgtttttgtttttgagagagtetegetetgtcgcccaggetggagtgcagtgg cgcgatcgcggctcactgcaagctccacctcccgggttcacgccattctcctgcctcagc ctcccaaytagttgggactacaggcgcccaccaccacacccgactaattttttgtatttt tagtagagacggggtttcaccgtgttagccaggatggtetcgatctcctgaccttgtgat ctgcccgectcggectcccaaagtgetgggattacaggcgggagccaccgtgcctagtat tgggtttgtttgtttgttttttgacttacttgtttggttctatagcaatggcaccatgtt tctgtcaccctagggtttgatttttggtgtttctaagacacctctgggccactgcacatg gctgaggtgggcttcgcactggctctgtcttccgttggacgeccacacatcggtttattt atgcattctcttgtccacagacettgaggtcatcagacatcttgaatgctcccgagceca ggagcgagcgtttctgagctttgacggagcagcagtggggctgccgggccetagggggag caaatggtcctcgtttctgagctgcgaggctctcccagagaataagccatttetccgggg cactcetgggcctcgaaggtgtttggggctgcgggggattgatttgtgccgacccegcag tgtaggagacgcctgggeggccttgcgggttgcttcgatggttctcggggctgagatgct tgtgtctctctegggcgagacgcctgctctgggcttetgttcctattttgactgcttttt cctcatggatttttcagtccagcatccctagccacgggccetttgtctctcatgtgtgca ggtgactcacggtgactaaaatcttctgtaattccttctaaaatgttttgccgctttgct gtecacgtttccacecttagtctctgaggggcctagtgtgtgtatggtgggaagcggggt cagccecegcctggaccgctgtgacagaaceccacagacagggtgacttacacacgacag aaacgtcttttctcaagttctggaggcgtggggaccccatctccaaatacagccacattg ggggttagggctccccacgtgaatttaggggacacttcagttcgtcccggcggggactgg ggacgccgggctgtgtgctgtgtcctgtgggagagtttgttcaccctgctggaggctccc tgatgagccctggc5tctgctaggacgtcattctctttactgattgaactegaaggatgt ccagttggegcattttcagggtttcccaggcgcactgggggtgggtcetgtgtgtccceg __ _....ctccagecagcttcgacecccagctgtg.cgtcagtccctcagctccgccccccagetgcg__ _ cggccgtccctcggctcegccecacagctgtgtgacegecctgcggctccgcccgcaget gcacgttcgtccctcggetccgcccccagttgctegteggttccctcggctccgccecct cggctgtgcgtctggccctcagctccacccccagctgcgcgtccgttcctcagctcagtc cccaagctgtgegtccttccctcagetctacccccagctgtgcgeccgecccttggttcc aCCCCCCtccccagctgtgcgcecgccccttggttCCa.CCCCCCCCagCtgtgcatccgt ccettggctecgccccgcactgtgcgtccatttttgactecgeccccggetgtgcgctca tcectcggctccgcccccggctgtgcgtcegtecctcggttccgcccccggctgegcgtc tgtccctcgactcggcccctcagetgtgcgccactttctctgtggcccacagtacctccg tetccgccgcttcacacccttctctttctttctctcttcagagagggttgttgggcaggc agagcatcccccgaggggacaagtcaggcctacggactcctggagccaggacctgecgta ggctggttagggcaggatgegecctgtcttcgtgggtagagccacatgaggggtcacccg accccetcagggetgaggggcacaggggcegaaagtgtggccgcccctgggggtctgcgc ctcttgtggagcccaggcctggcgcccaggtgggtggagtgtggagggggcacaggctgc acgaccccagcctggcctcgggettgctgggagtcgegtetgtggccggaggggectttg gtgtcaccaggcctctgtcaaaccccaagecgcatcctgggagggctgggtgggctgagc cgcccgctgccgtgaggcctctttgacctgcgctcctggaggacccctgacttcttggtt tcgctctgaatcttccatttaaaggaagaggagcaggttttaccatcegtgtggcctgat ttcagcagtttccagtcagggctagtcatttgcttgttttaaaaacattccgttacaatt tccacttcagtatatttgtggcactttcatttggttcatgaaagtcgcttttatgatgga attttataaaagcacaaagcttcccattgtacgttccgtttctgaagattctgtttacac acacatccgtttcaaagagttttggaggagcaaagtgggacacggtgttgaggaaggaca agaccagccgtctgc~ttacaggcttggtgccgcctttctcataagaggcacagtccgcat gggctggactgtcaaatgcatgttataaagatgatgtttttggtaacttgcgaatggaaa cgggtgcacggtcggtttggctctcctgccctgagatttattaggttaaaggaaactcga ctggagagcceggggcctcgcgccgcttgcgtctggcgagttgttgaagtgaagtcagtg gegctctgcaccttagcctggcecaggctecactgtggcgtccactcttcctcctetgac agtcatgtgtaaatattgaggccegtttgaactatcectgtgcggaaaaaaaggectgtt tttcacagggctgcctggggaggaggggggtggaaaggaaaacaggcaggggacagacgg acccggcetgcgttggcctggggtgacttcacggctccactgtcagcaagcggccgtccc gtggtggatcctgtccgccctgegaggacacctggctccatccacacctgggcctctgtc tccagccgccgaggccgtgacaccatgaggatcatgtgaggaggggcagagagaggcctc cgggaggccgtcattccagccctgccttccctgcctgggaggacgctgeggccgccacca cctggacgggagtggcctgtcgcagctgcaccctgcgtgggctegtggctgccacgetgt ttctttacaccttteteatatcctttccagaatctatctacegecggggagecagaagat ggaggaagctgtaccgtgccaacggccacctcttccaagccaagcgctttaacagggtga gtggeccccttgggactagtcectcaaggggccttttgttacttttaaaagcaaagagag aggaggggaggcacgtcccgctgagcccaggctgggctctttttggcgcccgagggcaag gttacagaaatgctttctctggtgcaggatgaggctttgactagggctgtctgaggcggg aagtgccctccgggcctttccctgcgtggtggctgcccagtgaatgctgtctgtgtctgc ctggctgtgtgactcttatcagggctcagggctcactggcctgaggccccagcctgcctg catccagagtggggcggccgcattccatcegcatgtagcgccagggtgtgtgttttcagc cgcacacagtgttgcctagtagctaagagtctccgtgaaccctggaagctccttcagccc catccctgcttgggcctctgtcttcccagcggccacccacgggggccctttccagaggac acttagcttattttccttgtttctctttatgatgcttttctagttcctatgaaatgggtg attcagatgcttttgtaattgttctgtttcacagtggaaggggaggtgtctgggtgtgcc ttggtggccctggagttggtcccacacagggagtgtcttgggggtgcgtggaagtataca gggcctgtccccactgcgggactccacacagagcccctgacagcccctcacaggagcggt ggccctggggctacctttgcattccacactcacctgccacgtggcctcacgtgtcaacct ccgctgggtgtacggcacctctgtctcctggagcggcctcaagtcacctgcccetccttc tactcccatggtctgccctctagaccatcaggaagttctgttcatgtgagccactcctcc 'tgcccctgcgtgtgctcggtccctgtcatgtggcaagagtgggtctggactcccattcct cttggggctaacacaggtgaggatgcaggacaagctectgagtgactgaagaggggtgtg gtgggaactaggctccaggagatgagcaggtcagcactaggaagacctggacattgcctg gagagcccagaggacttectggaggaggaggcatctgatcatactgcctgggaggtcagt gcagaggagatgccaggagcaccgaggatgtggcaggcacgggagagtccagccagtgtc tgggaggccctgaggacgaggttggggacaccaggaaatggggagcctaggcggctgtgt gcttagggcaggtgggtgtgggtgaacaggcagtttggctcaggctgggactcaggagag tgtggctggaggtggccacattgggaatatctgtggagtatggtgccagggagtgttgca gcacagagatcccgtccgcaccccagcccaccctggccgccttttctgaggacacacgtt __.gtgagtcttctggggctgcagaacacagcaccactaactggcagcttaaacaatggaaac.
ttgctctccggcagtctggggctggaagtccaaaacgaaggtgtctttatgagtcagggt tctccagagggatggtaccaatgggatgcatgtacatgaaagggagttgattagggagaa ctggccctcgggcgcacaagacgaagtcttacgataggccagctgcaggctggggaagaa agaagccagcagtggctcactecgagtccaaaagcctcagaagcagggaagccgacagtg cagccttcagcctctgccagaggctccagagcccecggcaaaccactaataagtcccgga gtctaaaggcccaagaacctggaatctgatgtcccagggtaggacgagtggcaggaagca tccagcatgggagaaagatgaaagccagaagacccaggaaaactgcttctcccacctgct tccgcctgctttgccccagccgcactggcagctgattggacgccaccgcccacccacatt gagggtgggtcttgccctcccagtccactgactcaaataccagtctcagggcagcgccct catagacacacccagatgcaatacttcaccagttctctaggcatccttcaacccagtcaa gtcggcgcctggtgtgacccattacagtgccgcagggctgcgccctccttcceccgcagc cactggtagctgcgggcagccttgttcctgtgctggcagaggaaccactcacctctgttt ccgtctccacatggcctcctctgtatctgtctettctgtcattctgcatgacggattagc ccagagtgaaccctacccacccagtgacatgggccagggctccgggcagcacagggtgtg gcctctcactgtgcagctttgaggagaaaagtccattctgcegatggcaggtgcagacca taagtgaccctccccctccccaccaccaccagtgagcaaaagcttttcctttccttcctg cagacactggaggaaagggtggcaggtggacccaccacagccccgctctgctgtggaggt acagcccttctgggcgtgtgaacgagccagtttcacaaacacagaggccaaggcgagagt ggcccgaaagcctgcaacctgactgctcagggagggcggctgccctgcagttcagcetgt ccgattcccgcctaattgtgcccgggctctgatctcgccacctgctcgtaacgttctetg tccggacctcagagccgctccatgtagtgctcacttcatgttaattgcaggaccactcag atcacctctgctgtcacttaaaaggggcatttcaggaggaaagcacttggttttgtgtga atcagtaagacttaaaggggaacaagcacccaggagaagagagacttttccgtcctcttt gttggtgaagegaggatgaaagagtgggcatccgtcgctggggactgggctccccgccca gctctttctgtgcacttgaaagcactgcccttggactttgagaaggaagcgttcagtggg ggagecaaagggagagagccagcgaggttctgaagaaggaggtgaggaggggctgcctcc tccatgaaggatggtgccgggggtggcagggaagcccactcagtggaacagaactgctgg gtcagagctggcccagggctgagcacttcttgcagaggagggaagggatcctccagtaaa tcctgaggaggtgattggttaattatcagcccaggaatggggggtgaggtgggtaggaat ccaggctgctggctcccatcacagtaaacggcaggtggattgaggttaaaaaaaaatcac agggcccggcgcagtggctcacgcctgtaatcccagcactttgggaggccgagatgggtg atcgcttgaggccaggagttcaagatccatctggccaacatggtgaaacccatctgtact aaaaatacaaaaattagccaggcgtggtggcacgtgcctgtaatcccagctactcaggag tctgaggcaggagaatcacttgaacccaggaggcgggggttgcggtgagctgagattgtg ccactgggcgacagagtgagactccgtctcaaataaataaaaagaagaaacctagaagct gtgcagatctctggagaaaaaccgggcagtgaggaccagagggtctttagactcagccac acagaattttcagattttttcagtttccaaattaaatgcaaaaaacatacaggaaagggg tttgtagcacgtaaaacccagaagagatccagacatctcacacttagaattgaagagctc ctacacaaaggcttttggtaaatgctgggaccgagaagctgagaaceggtgtgaatggtt aatgaagtaagactgtaattgtttagagatgaggacagcatgacetccacaggtgatcag ggaaacacaagacattttctetgtcaacatcaaagatgttaaaagtaattaaagccggcc gggcgtggtggctcacgcctgtaattccagcactttgggaggccgaggtgggtggatcac gaggtcagcagttcaagaccagcctggccaagttggtgaaacccegtgtctactaaaaat acaaaaaaagtagccaggcgtggtggtgggttcctctaatcccagctactcgggaggctg aggcagagaattgcttgaacccgggaggcagaggttgtagtgagccgagatggcaccact gcactccagcctgggcgacagagcaggactctgtctcaaaacaacacaaaacaaaaacaa aacaacaaaaaagtaattaaagcccagggttgctgtcatggggtctgccaaccctgggga tgtgggacaggcatggaccctactctctggaaatcacgcagaaatgtgcagcgatgttcc catcctgcctctcttcaaaagaaatcaccegtcatteggaggtttgtgtatggggaagat cagctcagcattatttttacaagcaagagtgggaatcgtgtctggagttagctactccct ttgctgtgaacaacccactccaccacgtggggtataaaccatggtagggccacgtctctg agctgtggctgctggagagccctctgctggtggcacatagggcacaagtgccgcagggac agctgggtggatggcccaagactttggcctttatcatgagtggacagaggagtgaccact tgggtccctggagaagaggctatagagagtgagggtggggaagggagatcagaagatgcc atccatgagcagcagtgcctgtcagatttggtccaagcagtgccctcaggtggctggcag aggccaatgcaattccttttcaagccagcatcaaagaattcctgatgataaataaatcag gcatctgagctcgcaatggaaaaccacaaaacacagtgggaagcaggatatcctgagtcc aagctggtaaaagcccagacagaggctccaaccatcagaataggtaagggtgtgacaggt ctaaaacatgaaaatgggcgattgaaaatatgagcaggaggccgggcgcggtggctcacg __. catgtaatcccagcactttgggaggccgaggcaggcggagtgcctgaggtcaggagttcg.
agaccagcctggtcaacatagtgaaacactgtctctactaaaaatacaacaaaaatttag ccaggcgtggtggtgggtgcctgtaatcccaggtactcggtaggctgaggcaggggaatg gcttgaaccagggagctggaggtttcagtgagctgagaacatgccactgtactccagctt gggtgacagagtgagactccgtctcaaaaaaaaagaaagaaaatgtgagcagggaggcca ggtgcagtagctcacacctgtaatcecagcactttgggaggctggagcgggcagatcacc tgaggtcaggggttcgagacgagcctggccaacatggcgaaactttgtctctactaaaaa taaaaaatcagccggacgtggtggcaggtgcctataatcccagctactcaggaggctgag acaggagaatcgcttgaacccaggaggcggaggctgcagtgagccaagatcgtaccactg cactccagcctggggaacagagcgaggcgcgaggctgtcggagggagggaatatgagcaa ggaacaagttggcagcatgtaagacgtacttaaaacgtttttacccattaatctatgaat tcctctgagtttctgagaatggaaacttggggtttaggttttatttttttaatgtcacat ttcctgaaatgttactattcaaatatagatttgaaacaagagcttttgacagagcttggg cagcctcacttacaaagcacacacgtgaggtctctgtggtgggtgccaacecttggcaga ttcacactgcccttgtcagcagatgtcctggcctgaccccaggtaagggtggctccccac ggaaaggaaccttggtcaatttgttttttgtttgtttgtttgtttttctttttctttttt ttttttttttttgagacacagtctcactctgttgcccaggctggagtgcagtggcgtgat CttgaCtCaCtgCaaCCtCtgCC'tCCtgggttCaagtgattCtCCtgCttCagCC'tCCCg agtagctgggattacagatgtgcgccaccacgcccagctaatttttgtacttttagtgga gatggggtttctccatgttggtcaggctgatctcgaactcctgaccgcaagtgatccgcc cgccttggcctcccaaagtgctgggattacaggcatgagccactgcgcctggccaatctt ggttaatttgtaaagatacctggtggctgtgaatttggtcttaactaggaccgtagtgtt gcagagtaagatgttaaatggtgacctagagaaagccaaacacattaggcacattatacc aaaagaacttgacttttaaataatggttttagaaatggaagctggtgttcttctgcgctg tggacgcggaggagaatggagcaggtctgcacagccaaagtgcctcctttcactccaggg tccaggcatccagcagccgaagcgcctcctttcactccagggtccacacatccagcagcc gaagcgcctcctttcactccagggtccacacatccagcagcegaagegcctcttttcact ccagggtccacacatccagcagccgaagcgcctcctttcaatccagggtccacacatcca gcagccgaagcgcctcctttcactecagggtccacacatccaacagccgaagcgcctcct ttctctccagggtccacacatccagcagccgaagcgectcctttcactccagggtccaca catccagcagccgaagcgcctcctttcactccagggtccacacatccagcagccgaagcg cctcctttcaatccagggtecacacatccagcagccgaagcgcctcctttcactctaggg tccaggcatccagcagccgaagcgcctcctttcaatccagggtccacacatccagcagcc gaagcgccctcctttcaatecagggtccaggcatctagcagccgaagcgcetcctttcaa tccagggtccacacatccagcagccgaagcgcctcctttcaatccagggtccacacatcc agcaggtgccgactggggcaaaactcccaatgccggcattaagctagattggcccggaat cagaggtcttgggtgggatgccccctctcacccatccctccttcgaatagagcccacggt cctggtgtggctctgtcatggctgggctgatgtaggtagcatgtgcagaggatgtggagt cggctcctttttcetgtgacgaagttgaaagcgatgatgcatgtgtgttttcttacccga tgcccactgtgtgct.gggcactgtcctaggtgetggtcatccggccccacccaaacaagt gggctgtgtgggcggggggagggtecccgggccctgacgtccegagcaggctcttctgat gagcaggagagtcccgtagagggtctggaccccctttgctcagcegcacctgatgcecac atgtgctgagggtcccggttcctcacgtgaactcagtgctgtattttetcttcagtcccg tttcctcacgtgaattcagtgcaggcggttcacagtacactgtatttcctcttctttttt tttttttttttttttgtctcctgcctcagcctcccgagtacctgggactacaggtgcecg ccaccacacctggctaattttttgtattttgtagtagagacggggtttcaccgtgttagc caggatggtctcaatctcctgacctcctgatccacccgcctcggcctccccaagtgctgg gattacaggcgtgagccaccacgcccggcctatatttcctcgtcttaactcaggtgtgag gtgagctctgtaataggaaggaaatttgtgaaaaatggtaaaagagggaaaagcatatga aagggctgtgtctggaaagaatctgaattggaggctctgggcacatggtgacagtgcaga tgcacccctttactcccaggaacactttgggcacttaggcaaggcagaaaatgtccaagc aggtcccgacaacattcattetcatgccttttgtaacatttaaacgttcatgaaaacatc gccaaacaagctgataattaccatcattttggaattgttcagaaccatgaagaataaaga aggatcatttaaaatcttgaaaaatactgaacaaagaatactaagataattgcaggctgc catgtagcagttcaagatgttcatgagtccgagttceccttctctgaggctgtcaggagg aggttctgtttgaatgaaggtcaggcagggggtacccccacacactctgcttagccctag acgggaccccaggctgctctacgcagagcgcagcaggagctgcagccccecagcccctgc aagccacggggcettgcctgaagcagcacctcgtcacccctgcccgatggcacctcccct gtgtcccctcatgcagagcagggttccaggcctctccttggggccactggttcccccaac cttgggatagacecaagaggaggctctcaagcttgggcaagcctggcgcccggaagggac aaggtgccggggccacctgttgcccggctcagtgtcctcttttgagaaggtataggtgtg,"_ _ ___._.
gaaggccctgcctgtcctctccgctggcccctcagtgtggcctgggcctgacgctetgtt cccacctgcagAGAGCGTACTGCGGTCAGTGCAGCGAGAGGATATGGGGCCTCGCGAGGC
AAGGCTACAGGTGCATCAACTGCAAACTGCTGGTCCATAAGCGCTGCCACGGCCTCGTCC
CGCTGACCTGCAGGAAGCATATGgtgagtggcagggctggggaggcccggggggcaeggg cggggtcggggcgtggcagccagcccattgtccaagcagaccttggtgaccctgggttct tcaagaggggccgtggtgccgtcctagctctgggctgcagcgtgagactcaggcggcagt cttggataggacccatcttcctgagcccccacaagcceccggcacactctgctcattggg gcatgaggctcaggcagcaggctcaggtaggacgtggtacgctctgctcagtgggtcgga ggtaaggttcattcataccccagtcttgaaccagetcttaaggactgtggaggtgaaagc caggtctgacctagtagcattgggcacgctgaggctcegaacatctggagcctctccctg gcatcccccctgggaagccatgcccagcctgtgatgagggcggcaccttccctccgccat ccccgagtgcttggacttgaagcatccaggcctttgggggccttattgacttttgcttat tgaaggctgcctctggcatttccgtgtggccccctgcatcccactgaaccacgggggtga ggcctggactgaacattcaactccctgggccctgctgcagcgtgcagtgggtgtgtctgg ggagggtggcttgtctgcatcttgctgtggcatgggaggaaaggcgcctgtggcagtgac gtgccctctcctctgttacgggataaagacagagtctggatcagggtgtcaccccaggat caccagccacagggatgggggaccacgcaggctggtgcatgcgttggcacagtccttcca gaggtccttcagctgcatctgccaaaaagcctgtaatgccctttgacctcataggtccac tttagcgtaagcaaatgagaccggccccagaaatgtggtcagctagaggcggagggaggc cagagcctgccacccagctgaccaccagtactggtggetccattatgacatatctgcagg cggaacccagaggcccttagaatggccccctgatgcttggttactgacaggatgcagett tgggacaggggagatgaccaagcattgtgcaaaatatccegttgtataaagcacttggtg gaaaggtcatggcctgcagtaccgagtggccacctccgtctgcagaatcataggtaatgt ttatgttctttatctaattcagtaaaatagcataacaattagatttttatatactatatt acagtatacccattgtaatgtgtaaatatgtaaatcataaatagtcttgaagtggccagg tgcagaggctcacacctgtaatcccaacactttgggaggccaaggtgggaagatcacttg aggccaggagttca~.gaccagcctgagcaatatggtgagaccccatctctacaaaaaaaa tacaaaaattagccaggcatggtggtgcgcacctgtagtgcccgctgctctggaagctga ggcgggaggattgctcgagctcaggaggttgaagctgcagtgagccgtgatcgcgecact gctctccagcctggatgatgacagactgtgaccctgtctgtaaaaaaaagttcttaattt taaaaagtcacaaagtgtttacagaagctacattgtaacacctgctctagcacttggtca tgctgccatctctgtgtctctccggcagGATTCTGTCATGCCTTCCCAAGAGCCTCCAGT
AGACGACAAGAACGAGGACGCCGACCTTCCTTCCGAGGAGACAGATGGAAgtaggcgctg ctttcttccggccgggtagagcctgggcatcacctcaccctgctcacctctgccttctag ccacgagtcctttctcagtcccatctgctctgcaggggtcattgtcttcaagcctggcca cccttccctggggctggggatgaggctetccagggcctcctctcaatccccggcagagat gagcagggtgagctggccctccetggaggctgctgggcagggatgcctccgtgaagtgct gttgtggttgcccaggggtgcagagcctcttcctctaaccagctccgggagttctcgaag gcacttagtgcagcagccaccatggccgggcacctcecacaatctggctgctgcacagag ctgagccctatctggggaaagcctggcgaggtggctgctgcacacacagcgtggcagtgg catggtccttggatttttgtgaggttttgtttgttgtggggaaggacttgttttattgct aagaagcattcagagagagatetcaaacaccagttggacttacagcccaggtttgagcct ccacacctgcacctctgcacgggggtgtgagagcctcactttcacttgatgcatgtgagt tctgtctcattgggagaccacagaacataaagcacttatgagaccacagaacataaagca cttagttcacacagtgcctcacgcaaaagagatgcctcacaaacaactgcctgcccacct gctcctccacccacctatcctctatacagatattcatccgtacatcatccattcacccac ctagccaaccaaccagccctcatccagccaaccagccatcctecacccgcccattctcca tccatccaccacctatccatctatccacgatccatccatctcgtcatccagccagccagc cagccatcctccacrcacccatcctccagctatcttccattcgttcatetgttgtccact gacctctccatctatccatgtatctattgtccactgacctctccatctatccatctattg tccactgacctctccgtctatccgtctattgtccactgacctctccatecaaccgtctat tgtccactgacctctccatctatccatccatcttttgtccactgacgtctccatctatcc atctgtctgttgtccactgacctctccacccatctatctgttgtccactgacctctccat ctttccatctgttgtccactgacctctccatctatccatctattgtccactgacctctet atctatccatctattgttcactgacctctecttccatctatctgttgtccactgacctct ccatctatccatctatcttgtccactgacgtctccatctatccacacatctgttgtccac tgacgtctccatctgttcatctatctgttgtccactgacctctccacccatctgtctgtt gtccactgacctctccatctttccgtctattgtccactgacctttccatctatccagcta ttgtccactgacctctccatctatccatccatctattgtccactgacgtctccatctgtc catctatctgttgtccactgacctgtccacccatctgtctgttgtccactgacctctcca .._ tctatccatccactgtccactgacctctccatctatccatccattgtccactgacctctc catctatccatccatctattgtccactgacgtctccatctgtccatctatctgttgtcca ctgacctgtccacccatctgtctgtagtccactgacctctccatctttccgtctgttgtc cactgacctctccgtetatccatctatctattgtccactgacctctccatctatccatct attgtccactgacctctccatctatccatccatctattgtccactgacctctccatctat ccatccactgtccactgacctctecatctatccatccatetattgtctactgacctctcc atctatccatccatctattgtccactgacgtctccatctatccatctgtctgttgtccac tgacctgtccacccatctgtctgttgtccactgacctctccatctttccgtctgttgtcc actgacctctccgtctatccatctatctgttgtccactgacctctccatctatccatcta ttgtccactgacctctccatctatccatccatctattgtccactgacctctccatctgtc catccactgtccactgacctctccatctatccacctattgtccactgacctctccgtcta tccatccatctattgtccactaacctctccatctatccatccatctattgtccactgacc tctccatctatccatccattgtgcactgacctctccatctatccgtcttctatccaggcc tccattcatcccccatctagtcatcctccatccatccaccagacatccactcctgcccct acccacccattcactagacaccaaaatccggtgacgaattatttgcagatggacccctgg ggacgtatgtcacgaatgtacatccccaggtcccatggtcagagtcggcaggtgtgagtg gggcccaggaaactgcattttcagaagactctaaattagaatcagacatggctgctgtgt ggattcacccttcaccgtcaccctgcagaggagcaaggtccacagggtcgctgtgttccc agtgcgttectgaccacaccgtaacgcccettecttcetcectetctcaccagTTGCTTA
CATTTCCTCATCCCGGAAGCATGACAGCATTAAAGACGACTCGGAGgtgagtgtgtggag cagctcgctgccatttccgacgtcctctggaaagtctgtgagcctgtctctggggtagtc acggaaatctagatgtgaaatagacatggtccggggtgttgctaactaatcttcacgggt gtggatgtctagaaggaagtccttattcttgggtcttacttcaggcatgtccttgatgaa tacctgcaggcagctgtceccgcaggtggtctggggaccacaccctgcgggggaagccgt gccccacatcctctccattcaggtggtacagtggcccaggggctggcttttgagctgcaa tttttatcaagttgtgtctgcaccatgccttccgaattgtgttgcctcatttggccatcc tggcaaacectctgaagccctttcatgtccttccccaacttgagccaagaggctcaactg agcctcacgtctgtggccagctctgcaccataaaccctgagaagggaacagaagagcttg ctgcgttctcagcctctgctcgtaaaacccagggaaggactgcactagcgaagcccactc ctttccagagcaccaacaagtgtcaccctcacaactcgtgctccttcctggccatcctgt gtctggagggaggccggggcacttagaaagcagaatctgaggctgagcacggcgactcac acctccaatcccagcattttgggaggctgcgcacatcgcttgagtccaggagctcgagaa cagcctgggcagcatagcgagaccctgttcctacaaaaataaatacaaaataattagctg ggcatggtggcacgggcctgtggtcctagetgcttgggaggctgaggtgggaggatcgcc tgagcctgggaggtggaggctgcagtgagctgagatcgcaccactgcactccagcctggg cgacagaggaagagtctgtetcaaaaaaagcagaatccggctgggcgcggtggctcacgc ctgtaatcccagcactttgggaagctgaggcgggcagatcacgaggtcaggagatggaga ccatcctggctaacacggtgaaaccccgtetctactaaaaatacaaaaaaaaaaaaagct gggcgtggtggcgggcgcctgtagtcccagctactggggaggctgaggcaggagaatgge gtgaaccegggaggtggagcttgtagtgagtcgagatcgtgccactgcactccagcctgg gcgacagagccagactccgtctcaaaaaaaaaaaaaaaaaaaaagcagaatccattttgc cgcacagaacagcacctcccaaggaaccgcctcctccaccccgacctccttgccaggtgt agcttgcgggaggcagaggcttctgttcttcctcggagcgcctttctcctgggtatttct aataattatttctaataatgtgtgcctgccggtttgggagctcttggcaggcattagetg cattegctttaccttccttcccctgagggagggcactgatcaggaaggatgggcccaggc cctgggccacatgtccctgtggccacctcttcagccccactgatagggctgagggcctgg gggtccctcccacctgcagctgtgaccagagccatggtctgtggaacgaacagettctag ctttctagcaccttcctcagaagcacacagccttaaattcttacctttcatgccccagtt tagatgggagtttgggggtgggatatgtgggacgcagaactgagactcgaatcatgaggc cctgggctctgaggagcaggtctctgttgggaccgcatgagtgatgcgtggtcctctgag tctcccgggaacccccctctcactttctggggtcttgttctccctccctagGACCTTAAG
CCAGTTATCGATGGGATGGATGGAATCAAAATCTCTCAGGGGCTTGGGCTGCAGGACTTT
GACCTAATCAGAGTCATCGGGCGCGGGAGCTACGCCAAGGTTCTCCTGGTGCGGTTGAAG
AAGAATGACCAAATTTACGCCATGAAAGTGGTGAAGAAAGAGCTGGTGCATGATGACGAG
gtaggtgccgcttctcatggggcccgggggcccgggaacgegctgccctggggcctcctc cgggctttagcggaattaatccatgcacgagagacctagcctcacgttgacggagtttgt gcaaaatcaatagtcatgcatcgtgtaatgaccaggatgtgttctggaaagtgcctggtt aggtaatggcactgttgtgtgaacatcacagtgtgcactccacaaacccaaacagcacag ccaactccacagccaagatgcacagtgcagctcctgcteccaggctgcaagcccgtacgg __., _ ctgttagtgcactgcacactgcaggcagtgaggggaccaccacgagagcactcacgtgtc. _ _,.
taagcttagaaaaggtgaagatgggtatcgtggtctetgcaaccttctcatgtatggcca accactgatacgttgccttccagcagactgcggttgagttttaggatgtcatcacccttg ttaggaaatctctggggttgagctgaactggacgggtgatggggtgggacaggaagctgc ccagaggcactgccctgctccgtcctgcacaaggccccagctttgcagtacatgctgagc tgccgtggctctgtgtagcagatcttcccacaccagctgtttctaggggagaagtttgtt gattataggatcaatggtttatttgttgaaatctttttttttggaaacggtcttactctg tcacccagactggagtggcttgatcacagcccactatagcctcaaagtceccagctcagg tgatcctcccacttcagcctctggagtgttgggactacaggcatgagccaccacccccag ctgtataatttttgtattttttgtagaggcagtgtctcattctgttacccaggctggagg gcagagcatgatcacggttcacctcctgcagcctccacctcctcctgcagcctccacctc ctgctaggctgaggtgatcctcttgcctcagcctccagaggaaccaggactacaggcatg caccaccatgcccagctattttttgtgttttttgtagagacggggttccactatattgcc caggetggtctagaattcctgcgctcatgcactctgcccgcetcagcctgctagagtgct gggattacaggcatgagtcactatgcctggcctgtttgttgaaatcttaattctgacttc atagacctttttcttttaattaaagtaaaatacacatgacatagaatttgccattttaaa gtgtacagttagggccgggcgcggtggctcacacctataatcccagcactttgggaggct gagacaggtggattacctgaggtcaggagttcaagaccagcctgaacaatatggtgaaac cccaactctactaaaaatacaaaaattagccaggtgtggtggcgcacacctctaatccca gctactcagaggctgagacaggagaatcgcttgaaccagggaggcggagattgcagtgag ccgagatcacgctactgcactccagtctgggcgaccaaatgagactctgtctttaaaaaa taataaaatatgcaaacaaagtgtacagttaggcggcttttagcatattgagatacagag ttgagcagctatcacctctctgattccagaacattttectcaccccaaaaggagacecca tacccactccctgcttctgctctgcgtcagccccatggcctccaatctgccttcttcctc tgcggacttccgtcttctgcacgcttgacagaacggagttgtgtgtgagcttttggtgtc tggCttCtCCagtgtCCgtCCatgtggCCgCtCgCtCaggCCttCCtCtCtCtgCCtggC
cgggtaatgttccgttgtccagtggaggccccacgtttgtgcgtgcacctgecaaggggc attatagtgttcccacccttggctgttgtgagtggtgccactgtgaaggttcgcgtacaa gaatctgtttgagtetatttccagttcttttgagtgcaaacctagcagtacagttgctgg gtcacatggtagttctctgttcaactgatggggacctgccaggctgettcccacgcagcc gcgccgtttcacctccccgccaacaccacacgggcctgtttctgcaggtcctcagtgacg cgtgtgattgtgatgatcgctatcctggcaggtgtgcagtggtggctttgactcecatgt etctgatgactgacagtgttcagcatctttcatgcacctgttggcttctggtatttttgg tettttgctttcattcctgaatgcaggttgcgtctctcaggattagataaaaggccaacg tgtgggtggcagtaatgctgttgtcaccaagtgctgctagcacagaaggcaactggctgc tcgtcgagccccgatgggccacagagggggtccctcetcgccagccatgctcggggctgg gagggcagagctggggctggggctgagcctctactacctcccagcagggcgtgtetgtgc agtgcacaggctgtccaactggcccctcatccctgggtgcagaactcaaaagtgggtggc agcgtccatgccctgcgccgaggaacagaggccccaagaggtgtggtgccetgctgacag ccccgctgctggccagcggcagcacaggaggattccagccccctttgcagcacgtcccgg tcagctggaaagttaatgccacgtatgagagcaggtttgcgggaccctgagaaaagacat ttggaagagtcgctgctgcggttttgttctgtcttgaaatcatcctctgtgggccgggat gccgaggtggggactctggggttgtctttcgagaagagcctgattgcaggagttgttgaa tgcttggatggtttctagaaatttctttctccccacaaaaagactgcactctctggggcc aggcttgcctcttgttcccccaggagtcactggcaagccccttcccaccgattctgcagc gccagccccacgcag~ggccttgaactcagcagtgctgtgtccaggaggttccactcagtt tgggtgctgagtgatatgtgggtcatgatgccaacgccgacgtccctgeggggccacagt gggtgggtgctgctggtgagggccactgggggacgggtggtggcaggtgaggggtggagg agtcaccgccgacccactaggtcttcagccactggagatgggaggagatgcgggctggcg aggagctcggcttgtggcctggggtggcgtgagatacccgggtgcacatgttgagcagcc gtcggggygcaggtctgcagctcagggagaggecgggctgggagctctcggcgtggaaag atgagactcgaagccactccattggatctgcctccgaagagaagggagggtggccgagga ccaagcctcgaggaggaggagggcgctgaggaggaatgacacagtctcagaggctaaata gatactcactaatggtttgttgatttgtttccacgaaacttccgggagtgggggcaggca acacagtaagaccctgcctctacaaaaaataaaattgccaagtgtggcatgtatctgtag tcccagctcctctggaggctgaggtgggaggatcgctggagctccagaggtcgaggctgc agtgagcagtaatcgcacccctgtgatccagcctattttgacgcatttctttcactgtca tttttctaaccccgaagacaaggggttgacctaggaaggcttgagaacttcgtccagctc tactttctggggtcaagatgagaccaagctgttggatctttgtcactctaaagttgactt tgaccttgcagcattttgctgaactgcagcatgaattgggagggtgacagtcctatggct _ gaagctagtgctctggtgatgggtgtgggcttatcactcggtagcgctgggaccttgggg aatctgcttagccctccacctcaatttccttgtgtcctaactggagataataatacctgc "
ctcctggaactgttagggcaaagcctggaggccagaggccagtataccaccagaggccag catacaaccagagctggtagctttggtgatcgtggtgaagatgatggtgatgatgatggt gacaatgatggtgacgatgatggtgatgatggtgatgatggtgaggtagtggtgatgacg tggtggtggtgatgaagatgttgatgatggcggtgatgatggtgatggcgatgactgtga tggtggtggtagtgatgacattgaggatgacggtggtggtgatgatgatggtagtggtga tgacaatggtggtgatgacagtgatgatggtagtggtgatgacaatggtggtgatgacgg tgatgatggtgatgacagtggtgatgatggagatggtgatgacggtgatgatggcagtgg tgatgacagtgacggttgtgatggtgatgatggtggtggtgatggtgatgatgacggtgg tgatgaaggtgatggtaacagcgacagtgatggtggtgggggtagatggtgccaatggtg atggtggtggtggtgatggtgatgacagtgatgatgcagatggtgatgacggtggtggtg atgatgacagtgacggtgatgatgacagtggtggtgaaggtgatggtgacagcaacaatg atggtggtgggtggaggtgggagggatggtgacaatgatgacggtaatggtgacagtgac gatgatagtggggggtgggggtagggtgtatggtgacagtggtgtgacggtggtgatgat gacagtgacaatgatgatgatggtggtggtggtggtagaggtggggtggatggtgacaat ggtggtaatgcagttcctaatgggtgttttcttttcctgtctgcattgtcttcetgaaag cggaggaaagagactcctcccttgcctcccccttgcccaggatgcctgtgaggagcattc gggagcctcattaccactccctggtttetatttcagGATATTGACTGGGTACAGACAGAG
AAGCACGTGTTTGAGCAGGCATCCAGCAACCCCTTCCTGGTCGGATTACACTCCTGCTTC
CAGACGACAAGTCGgtaagaaaaagaagggtatttctgatattctgcagatttcagatgt gaactgcacagaagctaagtctggtgtgatgtgtcaactgtcacctgtaaggttctccca gttgctgtacgggtgttttcaggccagcagactctctttgttgttctccttggttggtgt catattaagtacatttcatgatctgaagttatttaattccatttacgaaatacttactgg aggtatcccactgagtgcaggcattgggtcaggtgctggggctacaaaagtaagcaaaag aggtggatttctgtgcttattaaaatatgtacagcttcaccttcaagctttatatatact ggaattctgtggctttgaatacatttgaaagctgatgatctaggatattaaatgtatgcc ctgtttaaaattttgggggccagttgactttgacctacctgatttgtttatttgaagagt tattaagtatgttctgcattgagtcctcaagaccatccccaggttcgatgattggctagg aggactgctgggatcaatcatggccgcactgggggccacagetggcatactgcactgggg agataaaggagacttggccaaggaaaaaggcacatggggaaaattccagaagaaaccagt cacaagctcccaagagccctctcccagttcctccagcaatgaattgtgacaactcatggt ttttgtcaagggctggtcatgcaggctgcacacgaaccaaaattccagactcccagtgga gagcaggtgttcageattgcgttagtcagggttctcctgagaaacagaaccagttgtgtg cacgtgtgtgtgtgtgtgtaaagagatttattataagatactggttcatgggattatgga ggctgagaaatcctataatccgccatctgcaggctggaggcccaggagagccagtggcac agcttgaaggcctgagagccaggagctgatggggtcgcttccagtccgggtctgaaggcc tcagagctaggagcaagggggccagaaggtggatagctcggtagtcagggaaacgcagcc ttcctcctcettcttgttctcttcacgtccccaggggcctggatgatgccagtctacttc agggagggccgtctgcttactcttccagaagccccctcaacaggcatgcccggaagtcat gtacagccagctactagggcgtcccgtgcccagtcaaggtgaccgttgaattcaccatca cgagcataaggcatcctgttcaggcacacacagtttgggcacagcaagcagctcttattc caaagctttttttttttaatgtgcttttettgtttttgagatggagtctcgctctatcac ccaggctggagtgcagtggcaacatcttggctcactgcagtcaccacctcctgggttcaa gcaattctcctgcctcagcctcctgagtagctgggattacaagcacctgccaccacacct ggctaatttttgtatttttagtactctgtgttggccaggcgggtctcgaactcctgacct caagccatctgccctctgcagcctcccaaagtgttgggattacaggcatgagtgactgag ccccgcctccagagtttttttttttttttttttaaataaagatagggtcttgctctgtcg ccccaggctggtctcaaactcctgggctcctgcctcagcctcccaaagtgctgggattac aggtgtccaccactctgcctggcggtcatgcagaagcatgttatatccgtgtagggaact gtttgcagttcacgttcccagccccagctccgggecagctttgcgggccaggcttcctaa gcacagcggtcctaggccctgggtgcaaccctctgctgctcggttcttagctgtacatct ggcgacttgctctcctccgctgcactcttggctctcctgaccgcagggtcctgctcttgc ctgtgcttggcagccacctctgtctgtcggaagagccggcgtgacccggcegttccccga cctgctctacgtgcggtgccgtcctggtcaagggttcctgttttctggctgcttacgcct cctaagtgtgtttcagggtcccccaccctccecacctgaccccagggctccccagtgttg gcttccccatgttgggcctgagccatatt'tgagaaacacagatctgaagtctttttcctg cctcaaagctcctctgattcctcctccccagttgcttctggggtaaattccaagcttcct gtgcgtgtggacgaggcttgtggtgaccaggccccagtgccccatcgtgtgcttcagcgt ggcgccctcgcccgcaccgcctgcgcctgacggctctgtcccctttcettctgctcccct __..__ - _...gct cccggagtgagtcaatgcctccctttgtgcattcccattgcgcttttecaggcctc.~
tttccgccctgactgccatcccttgcgatttgggaatacgcccaggggaaggcagcccgg ccccccacacttcctaaatggtgaggttccaagaagggttttgttttgctttggttcttc ttcatatgtgaacttgtagggatgtagatgtataaggggtccgatatcccaccctcactt cccctgagtggeccaaagctcagccccttctgcacttgtgtctttggactcttctgtcaa gtcacaagttcccagatgcgtaaacctgaacttaaagaattgtcgtctgtggggtgtctg tgggatccccgcagcggcaccaatcactgtcctgtgggagcattcggcattcacagttgg gaataattcctatgcatgtctgatttttttgccttttttttttttgagacggagtcttgc tctgtcacccaggctggagtgcagtggcacgatetcggctcactgcaacttccacctccc tggttcacgccattctcctgcctcagcctcctgagtagctgggactacaggcgcctgcca ctacacctggctaattttttgtatttttagtagaaacggggtgagctccgggttgggggg aggaccggcagctgcettagtccaatagctggggggctgtgaaaactgcccacaaattct tactgaccacacagcaccagacacccacgtgaagcaaagccaacatcggcaaggcggcca cgcgtccgggtggcggaaaagtctggcctggcccaggtgggtgtgctcggctgtgecgcc tctgctccctggtcactggaggtgactgcaggctttatgaggacttcctetttgtgcgtt ggttctgctggaacatccagctgaggttttgcgtgggccccttgctgagggccaggtgaa taacacgcagaacaggacactccttcgctctgggcggcctcacagctcccgggccatatc cagggggaacctggccgatgaaactgcagaggtttccacacaagtttggttcccataaag ggtctgtgagtggggaagaatcagaattgetttctttccaccccaaatctggtcttgcct cttctggccggccatgttcgtgtccactgggcggctacagggaattcctgaatgttacag ttcaacattagtctcacetcgtgtgtccagatggagagaaacaattcattcgcagtttta agacacaataagcacctgctttatggacaaaccataceecatatctacacagacagccea ccttttccagacagcagccaaaattgaaatgagccataaagtetccaaaacgagaaatcg cttcagtttaagctatttcaggaaaaccaggtaactagagatttagctgaaatgactact ttcagcgtcccccgccccattcaactggagtcggaggacactttctcactaaggcacggt gatctcagatggtaggtgagcaaactacccttaaaatacgcccattcactcgctgttcta aaataaaatctcttactgt.ttgccacggttgattattttacattcattcacactcaatgt ttctttaaaaagaacaaacacacacctttgcttatctgtggaagcgcttctcaggccgtg cactgactgagacacttgagtaagetcttcttggtcaaactgacttctagacatgaaaag cacttcacccagcagtgtgcgtgtgtgtgtgtgtgtgtgtgtgtgtgtgtgtgtcagtta tgctttgaaacctgcccgaagctctggagagggagacagctttactaacagcagagagtg acgtccctggaactggtcaccagcgtcaggaggcgtggcacccggggagggtcegcaggg agcagagtgggactccgtggagaggggggcaggcaagggttgggtcacgtaggaggggct catgggggacaggcctgtgggaaggacgagggcaatggtgtgtgtcagggacagaagaga accaggcctgaaggtgccaggggctttcgaagctggacttggccaagaggccctgggatg cggaggccccagggattctcagtgcagtgctggtgttgggcaggcactcgtgtgaggagt aggatctgggccgcagaagccagagggacctgctgggcctgtcatggcctggagggaagc cttagggggtggggaggaggggcctgtccccatgtgggggagtcaccccggttcgcagaa gtcagggcagtgctggccagacaggcacagagcggagccagcctggacgtggaggactcg ggggtgctgtggcctgggatggagacgccccgccccgccgggggtgattgtggttgtggg tgtgtgagaaagaggtgagggtgtgacggggtctgaccctggggtgctgcctcctcaggg ctgcaggaggaggcgecgccgtcggggtggaggcagtagagggaagggctcagtgggtgc cacagcaaggacagcctcggccgegaccttgggaagggcaggtgcctcttcttggggaac atgagtcacctccctttcaaaacccatccgtgtgctggagtcatgggagctcagaacaga aggagagatcctgactgacacccgtagggcccagcgtgggcgcagccgcctcagcctttg ttctgccgacacacggtgacggctcageggccccctgatttgctcacttttcatcggggt tgcctaaaatggtaaaagtgccaccctaaaccctagcacttccggagcaggacgcttggg cctgtggcccccacaaggctgtgcacgggagaaggggctcttcccag'catcaggggcctg gcaggagccaggggcttggtttgccttttgcattgcgagggcgtcctgcactcttcggga acactgcggacagctgcgcatgcatcctcccagagccctgggcagtgaggggccctcggg gacccccaggacatgggctttgggacacacctgcagtgtacagggggccctgctgtttcc tgatgtggtgtcacaggccacacaggactgtgcagaacacgggagaaagggatgcgttgt etgtagttctaatcgggaggcactggccgctcttagaacaggtcagggggcaggtgtcat tgccattcggggtcacgttaggaccgggggacctccactgcaggcttggagatgattttg ctagtagtgagcagagatgaggtcatggcatctccccttetccatccagacccgaacgtc ccatgccactgcgccctgcatggttcccaggatgagcagggataggggtggcagccctgg agccacctggagtctccttagttgaaggaactttcaggaccggtcctgaaattgtgcett tgctgcttaactactagataacgacagagaccacataaaacaagagcctctttataaact tgtatcccattttaacgtgcaggaaagaaccttcgtccgcactccaaagacccttgacta accagcgtcaccatccagacagttttgcctcgtttttccttttctcttgtttatttttcc _ atgtggactttataatcaacccgtctgcctccagaaagaaaaagaaactgggattttctt ttcttttctttgagaaggggtcttgctctgtcacccaggccggagtgcagtggcgcaatc ttggctcactgcaacctccgccccctgggttcgaggaattctcatgcctcaaccccccga gtagctgggaatacaggcccctgccaccacacccagttaatctttgtatttttagtagag acggggtttcaccctgttggccaggctggtctcaaactcccaacctcaagtgatccacct gcctgggcctcccaaagtgctgggattacaggtgtaagccactgggcctggeccgaaact ggcattttcattgggatttgttaagttcacacattacctggggcgaaattgacatccttc taagtgttggatcttcccattcaggaacccggtttaccttttcattcactcacatcctct ttcaggagactcttgaagtcttcatgtggttttcttcacttccttgtctaattattatta ttattatttttacagatgggggtcttgctatgttgcccaatctggtctcaaactcetggg ctcaaacgattctcccacctcagettcccagagtgetggcatttcaggcgtgagccacgg tgcctggccacttccttgtttaattttgtcttgagtgtttcatctcgtttctgttataaa cgaggtattttttcttctctcagagcatccagcagcaggcagcttggtctctgcgtggta actgtgggccccatggcttctgagttctcttccttgtagtaactttcatggcttctgagt tctcttccttgtagtaactttcatggcttctgagttcttccttgtagtaactttcaggtg gttttctggggctttggatgcacagggttagcatctgcaggtggggcagcatcacccacc tcagccgctgcaaccaggtcgtgccgtctctgttcatcttcctctctggtgacagtggcc agcacctgcctcactggggtgacgttgacactggacggccctgtcctattcctgacccca gctggaacactttgcaccggaagcgcagtgccatcctcaaggcagaacggaagcatttac ccatctcgggcaggcagcatttgccctggcatgtgcaaagggtgttgggagggccacagg ggagaggagagacaggggctctgcctgcagccgtggaactgggttctggagcccacagag gagctgtccctgcctgagctgttggagacgggaacggaccctcccagttcctgggcccat catctggtctctgaggacacctgctggcaaaggccctggcaatgatacatacagcctctc agcccccagccactgggagaaggttctagaaaggctgagcagcagcgtgaagctgagaga agatgaccgataactgcatgcagaggtgtgacttgtcctattaagggactttccacccat ttctgttttgctatcaagaaaaaacactgaggccgggtgcggtggctcacgcctgtaatc ccagcactctgggaggccgaggcgggtagatcacgaggtcaggagatcaagaccatcctc gctaacacagtgaagccccgtctctactaaaaatacaaaaaaaaaaaaaaattagccagg tgtggtggtgggtgcctgtagtctcagctacttgggaggctgaggcaggagaatggcgtg aacccgggaggcggagcttgcagtgaacggagattgcaccactgcactccaacctgggcg agagagcgagactccatctcaaaaaaaagaaaaaaaaaagaagaacactgcaagttgtgc aggggcctccttgccatttgtggagatcattgttacgatttttactccttagggcctcct ggaatgaatggtgtcatcgtaatgtagctgetggtattgaaccatccttagattcctggg gaaaaccgtgccctgtcttagtgtgctactctgttaatgtgcttctgaattcaatttgct gatattttatttaggattttttttggttgatattcatattgttttagtttagaatcttca ggacacagagctactgctccagtgatcaagggagacacaggatggaaacacaccttttgt cacccacaggcettgggggtacacaacctgctgggaggccagggagcgtaaagagagaca gggaccctttattgggtccagggtgttctgcacacaggtttcccatgggaagttttaact gatggacttaaagcaagcaggcctgagctccgtggggccacactgtgactgtcgggggac tctgcagtgtggctgcacagtccatgttgggtgtggtatcagtggggctgcagggaagtc accagggggcagttgcatagggtgggtgtctggatgggccagctcgaggaatgggggatg tggaactggaaactgtcagggegacagccctgettctggtgggagaaagtecagcttaga tccagaatggatgccgaggcagcctaaaaccatgagcgttccctgcacactctggcgtct gatctctagcttccctttcttgtgcaagcttcattggatttttaaattttcctaattttt caatteccgggaacattctaaattgcgttattacctcttggcgggatccctgtgcgattg ccgggccttgggtgtcgtggagggcagctgcctcgctccgccctggctttcgtgatgttg tgagctttaccctgccgaggctgggtgttctcacccagtcccacggctgcaccctgcctt gccttctcctctgctcaacttcaccccaggccgtgtctcctggctccaggaaggtgaggg gctgcctcccatgcgtcctttcatgttgaggacacccgtgtttgcctttgcacgtgagcc ccattgtcgctgggacacactgccctccagtgctcgagtgcatttcctgggcactttctg gccttttatctttgatggagaaatccgaggcctgccagcatccccaccagtagatttctt tggacgaagtaaaatccttctgtggattcagctttaccgcctttcctcatctgctggtgt ettcctcagagctttaatgtccgtcctgctctccgagtcaggaatctgattttccagcgt gccctgtaatgacggtgctgtcaccgctgtgatgtccgctgtgaggtggggacaggacct ggaagtggggtttccaagtgagggttctgggcccgcccgagtcatctgatgttgggtctg acaagccaggagctgtgtgagccggagaacgtcccctaacctgtctgtgcctcggcttcc ccatctgtaaaatggcgagagctgaacttacttcctggtgatggggtcaagtgcgttaac acagagggacttggagactgacgcttactgagggccacaccagcggtcagcaaaggttgt cttaaagggtcaggcagtaaatatttccacctttgtgggccatgcggcctctgtggcaac tatgcgttctaaaacagaagcagccttagacactgcgtgaagggacgcgtgtggccgtgt _. . ____ tccaccagaactttctgtacacacatggtggtggccegcccggacccatctggttaattc __ ttgactctcagggcagcgtctcctgtgcctccaggagagggctgtggttcctccctctga gccgggcaccttgcattcctggaaggggtggggggagtggcgaggagggggcggcaccaa ggacagggcccacctcctaggaggttttgtgagcttccctcagcccccggccgeccccta ggaggtttcgtgagcttecagcatccccctgcggccactgtccctccatttcccatgtct gttggatggtgccggttecagggcagggtcagggactggatccggctgcggtctgcgtct cgcctggttcctgagagctgcactttgtctttggttgttgatgaatccatttttgctggc gttcttcacgtttgtgtatttgattaagtatcatggacaggcatgtgcagtggctcacac ctgtaatcccagccctttgggaggctgaggccggaggatcacttgaggccaggggttcaa gaccagcctgggaaatatctcgagaccctttctctacaaaaaatttaaaaattagctggc ggtggtggtgeaagcatgtggteccagctcctcgggaggetgaagccggaggattgcctg agcctgggaggtcgaggctgcagtgagccatgatcacaccactgcactccagcctgagtg acagagtgagatcttgtctcagaaaaacagccccgagggcacgtgtctcatgactcccgc ctcccgcctcccatctgggctctgcttgctcctctccccttgcaaacatgagaggagcgt taatgccaggacagggagcagggaggggcatccccagcgcctccaggccacaacatggcg agtgtggctaccaggacacggaggggcagcctcagccccctcccccaggccacgacatgg cgagtgtggctaccaggacacggaggggcagcctcagccccccccaggccacgacatggc gagtgtggctaccaggacatggaggggcaccttcagccccccacccccacccccaggctg tgcttcccagcatcccttggggtcaggactgtgtgtgtcactgaggggctacgggtgaag ccacacacgcccctggcctggccttgcgcccctgcctgagagcctctatgcaggacagcg cetgtggggcacecaagtgggccgagcccatgtggattacaggtgcacaccaccagcgtg aggagaggagtgggetcggagcatgetcagccatggtcccaggcatcttgtcagcagcca gctcagcttgtgtcacgcagagtegccttagagtgaattgacaccagattgtcetggtgg gtttttgctctgaagaaatgtcaaaagtagcattaaggtttttctgtagacaaaaaaacc ccaccatcattgcagcttgagcagttgcaaattaaataaattccttcctcagcaagctgc ctgggtcctaggccttgggcagagagaactggctttcagcacagttcccgtgattggctt ttctctggagaagaaggggaagcggcctccgcctctacctctctaagtgtttaaatgtcc cccaaattctctcagcctcctgaggcattgtattgatgcttttctctagaattcatgtat ttctttattttctctggaaatggcattggctttgtccccgtcctatgggccgtgatagct taaagttaggatgaacccacagaggccgtggaggcccttcccaggcgccgcagcagcact gttggggtgaacgtggctcctctcggggggacaggtggaagggaccagcacccattgggg cgtgtaactcctggtggcaaaaaatgtgcggtgaagtcaccctaagggtttttgtggttt tttgtatttttattttattctttgagacagagtcttgctctgtcgcccaggctggagtgc agtggcgcaatctcagctcactgcagcctgtgcctcctgggttcaggcgattctcctgcc ctcagcctcccgagtagctgagattacaggtgcacaccaccagccctgggtcatttttgt atctttagtagagatgaggtttcaccatgttggccaggatggtctcgaactcetgacctc aggtgatctgcttgccttggcctcccagaatgetgggattacaggcctegtgagccacca cgcccaggcactetaagggttttgaataaattctttcttaacgttttctgaccgactctt aggtcgtgggtgtcctccaggggttggaggccttcatggagcttcgttccgtggggttga cgttactgaacgagtccctccacgggtgcactgaggacgttcctgcacatcgagggcacc ctcagagctgctctttctgtcattgctattttgtttataccggggattggcaaacttttt cttgaagggcccaagagtagacatttttggctttgcggccacagggtctctgttagcaac tccctctyccacggtggctggaaagcagacatagaaaatagatgcaccagtgagcatagc ctcgttccaataaaactttatttacaaaacagggagcagtggaccagcgagtceccaagg acaagggccaggttaccagagaatttccaggcacatccgttggaggcaggggagacaaca aaagccgaggaacgagccttccccagccgctccccaaaggcacggcttattcttcagggt gcccgactggccacgtggacgtctctecagctcctcacttggggcccagggctctttcga tttttaggagtttgtttccaatcagaaacttcacagatgatttgcagccagttcacctgc cctgtgtaaactggcctctgtcctctctggcttaattctgggagcttgtggagggcagga gcagggacaggtgccttgaggcgtaacagtggcggtggtgtgggagcttgcgtgggatcg aaggaaacgggcagagtcaccacacgcttccctccttcactccccgctccacgaggggca gccaggagcagccaccagtcggaagcaaataaacaattcaggtgccagaggagccgctga cctaaaaaaacccgccacagggtatttetgggagattgtatgagaatttaattttgaaaa ttgagtctcatgaaatgtaggaaaagatcttattaggaagagaaaccatgtggcccagtc cctgagacgggaagggcctgcgtggtcctgatgacatctgcggatcttttaaaatcatac gatcatgtctgcgaaaccgggatgccacttcccacctggcttctccctgaccccagcttg ttcccttggagggceggtggactcctcagccttgcagcaatgaaatcaggccttgaggcc accccacccgtgacctgcggtgctgtccccatgcaagaaactgcetegctccagceccca gcagatcctgtcccagcccccagccctggtccaagccacctccactcccacctggtgacg ggccacctccttcattccggggcccacccacacttcccaagtccacacacagtggccaag agtgaaggccggcgaggc. _ccccgcatgac ccctcacctgcacecttcacgagcggcccc gcagcccgtccccaccagcccctctctgctgccagggtgctcctgctgctctttgctctt tgeaagactgaacctgcgggagggttcgggcccacgaaggccgcttctgtggggcttctg tctaaggaggccgccgtctgccgaggtgactgcagcctccggcgcctctctcectgcagG
TTGTTCCTGGTCATTGAGTACGTCAACGGCGGGGACCTGATGTTCCACATGCAGAGGCAG
AGGAAGCTCCCTGAGGAGCACGCCAGgtgggtgcgcgtggaeggggccgggtgggtgcgc ccggagttggggatgggtgggtgcgtgcggtgttggggggctgggtgggtgcgcacagag ggatgacgggtgggtgcgcgcggagttggggggccgggtgggtgtgcgcagaggggaggt ggctgggtggggtgtgcacggagggggtatgacgggggcggggggggcggggtgcacgtg gagggggccggggaccttctccaggggtcagcagggagctcaagggagggaagtccaggt aggatggcagagggcatcatgtcccccacagtgtgacgtcccctgcattgtgacacattc catatttgctccagagtcacaacatttgggaggtctcctgagttatggtgcctcagacca gtcccccaggecccacecctgaagcagcaccatgcctcatccgagagaagtgagagtctc ctgggattgtgctgtcttcatggtggctctgccctggttctgctcttcaccctgttagtg gcacagcatggccagcatttcctcagcgttaggagcagaacgagagtggtctgtttctag agtgacctgagagactccttcctgcccttccctttcatctctgatatcttcgggcctccc ctggcagccgaggggcctccagcatggttcaggagcctcceccggcagccgcgggacctc caggaccgtttgggggcttatttcagctccctggacctttcctgtcttttgtagtttctc cttttcctcatttccttacttaagaacgttgcatgcagttttgtgagtcaccttagattg tttctggcaataggacagtaggcaataaatctagaacagtacacttcccacaacgctgtt tttaaaaactgtggcaacacacaacataaaaggtagcattttggggcatggaattcagtg gcgttgaatgcaccccatgctttgcagccactgctggcccccgtctcatctccagagcac gcccctcttccctgctgaagcttggcccatcagacactccctccctgtcccccgccccag cctcacatcctcaccccagacgggcacgtcccactttctgtccctctgattcgaggactc tagggacctcatcggagtggaatcacagtgttggtccttcggtggctcattttcctgagc atagcgtcctcaagattcatccgtgctgtggcctgtctcagaattgccttcctttttcag gctggataatgccccgttggatggaggggccacactttgcttatccgtccatccctcggg gggcacttgagtggcatccacatgttggccatggtgaacagtgctgctgtgaacatgggt gtgaagtaatctcttgaacaccctgcttccggttctttggggtatacacecagaaactga attgctaaccacataagaattccatatttaggccgggcgtggtggctcacgcctgtaatc ccagcaciatgagaggccaaggcgggcggatcacgaggtcaggagatcgagaccatcctg gctaacacggtgaaataacacagtgaaaccetgtctctactaaaaatacaaaaaattatc caggtgtggtggcgggcgcctgtagtcctagctactcgggaggctgaggcaggagaatgg cgtgaacctgtgggcagagcttacagtgagccaagatcgegccattgcactccagcctgg gtgacagagtgaaactctgtetcaaaaaaaaaaaaaaaaaggtcatatttaatttttttt tttttttgatggagtctcgctctgtcacccaggctggaatgcagtggtgggatctcagct cactgcagcctctgcctcccaggttcaagtgattctcctgcctcagcccccagagtagct gggactacaggtgtgcgccaccatacccggctaatttttttgtatttttagtagagacgg agtttcgccatgttgcccaggctggtcttgaattectgacctcaggtgatctgcctgcct cgacctcccgaagtgctgggattacaggtgtgagccaccaagcctggcaccgtgtttaat tttcgaggacctgccggactgtcttccgcagcagcggcgctgttctgcactcctaccaca acgtgccatggctccggtctttcccgcatggaagctgtcgtgttatttgcccgctcctcc ccttgtggaggctgccacatcgttctctgtgtctttgacagcaggccatcctaaggcgca tggggtggtgtcctggagctttcattggcatttccetcectggccctgtgcactgcactt tcaaatcctgggcctggtcattgagaggatgccgggcccgtggtggggcaaacgggagtg tgtggcccecaggctggagctgttggcgcagcctctggcacaggcactgcccccatgacg gcatccccacccccagGTTCTACGCGGCCGAGATCTGCATCGCCCTCAACTTCCTGCACG
AGAGGGGGATCATCTACAGGGACCTGAAGCTGGACAACGTCCTCCTGGATGCGGACGGGC
ACATCAAGCTCACAGACTACGGCATGTGCAAGgtgcgtgccttggaccgcctcccctgac catcccgcatgtgcgtctcggggcgcctgtcccgcggggtagtgtctacaagaaccctet cccagtaactttgcccccacagGAAGGCCTGGGCCCTGGTGACACAACGAGCACTTTCTG
CGGAACCCCGAATTACATCGCCCCCGAAATCCTGCGGGGAGAGGAGTACGgtgagtgccg ctgccctggcccctctcggagcacacagggccagagatggcttcgggcctggcccagcag ccagggagaggtgtccttgaccatcttacacccaaaagecacacactgtctttcccagcc ggatgtcatcatctggcetcagccccttatttgaattctggaaaacctcccatgtccact tgagcagctccttggggagggcactgcacaggattcctcctgccagggagccccggggca cagggaggggaaagacacagaaagcgggggtgggacagggtgcagcacctgagtccccgt gctgcacgagtggctgggggagaagctgttgtctggggagccccagggggtgcaggagcg tgtggacaggaccccacaggccctgcggctgaggacgccgtgcacaccagagtgtttctg ctcctctcccctctctgggcgtgaaacggggacatgggcacgcgtgtgcagccgtgtgtg cgtgtgtgaaacggggacgtgggcacgcgtgtgcagccgtgtgtgcgtgtgtgaaacggg gatgtgggcacgcgtgtgcagccgtgtgtgcgtgtgtgaaacggggacgtgggcacgegt gtgcagccctgtgtgcgtgtgtgccgttgggctgagtgttcgtgtgtcgggcatccatgt gtgttgtgtgcacatgcatactgtgtttgtacacactccacccacttctgcatectggtg ttttcaatgaggcatgcatggtgtgccttcagacatttttacacattttttttgccatca gaatgggtgtggggcaggcagggcgggcaggtcactcgccgctgggataactgggctccc cagcggccacaatggaagtctcagtagccagagaaggacagacagcagattggaggactg gaatatagtctagaacccagcttgggatggggattccgtgtgggacagcggcagcgtctc acctcagcagggaccagggggacttccggggacgcagagacagctgctgtecttgggcaa aacgggtcagggtctcccacccctcattcgctggaacacattcccaacaggttgactact tgaacctttttaaaaaacaaaatggctgtagaaggaaacacaggagagtatttccgttac tgcagcgaaagggcttcttcaagcttagttctgtagaagcagaaacgagagaggagggtc gtccgcaggttccaccagtgcctcgtgccggtgtggtcacaggtgccctggcaggaccga cagcccagaggcagectgggagacctccgtagtgtcagggacggtggcagggaggccgag ctgccaggtggaggtgctggttctgtttgggaagtggaagtcacagaggcctgtgtgceg cctgctcaagectggctcacactcgtgtcaactgggcatgaaaaccaacgccagccaggt tcgtcctgctgccggcccatgtggccccactcggtgatggctgtgtgctctcccecagGG
TTCAGCGTGGACTGGTGGGCGCTGGGAGTCCTCATGTTTGAGATGATGGCCGGGCGCTCC
CCGTTCGACATCATCACCGACAACCCGGACATGAACACAGAGGACTACCTTTTCCAAGgt gcgtgccccgctgtgcgttcgtacccctcacctgcacgactgtcttccttccttttcaaa ggtgcaggtggaggggtcccgcgggtgcctggagcggcagtgccatgcaaagcgtaccgg gaaccattcctcctggccagaccctgtgtcacatgccactccccgggccgtggggtgggg ttaccacacetgtgggtcagcaggaaagagaacctgtccccattcagctccaactccctc ctgccctggccagcagcacatgctggagccccagcatgtccttgaccgaggctgtaccga gctgaaagcacagcccccacccccaaaacccacagccaccatcatgggctccttcccacc tggaggccccgggacctgctcctggtctggaattcagtgctgtggggatgtgggatctgg gaacgcggctgtctccgcggtgccctctggtggccagcctgcagaggcacccgtgtacct gcgatcttggggctgaggaaggggagctgctggttcacgtccgatcctacgacacgtgcc agcgcatgtaaccaggaggcccagggaggacccggcgggactcegggttatagatattgc tgggctgtaggaagggaggggctccggggccccaaggctgagctcccaaagctcttgctc agagtcagagtctgggcggcactgggcaaatggcacacaacacaggcaagtcctcaccag gctccgcccttgcagTGATCCTGGAGAAGCCCATCCGGATCCCCCGGTTCCTGTCCGTCA
AAGCCTCCCATGTTTTAAAAGGATTTTTAAATAAGgtacgtttctggccatgctgacaaa atctcgtttgtggcctcggtgttggtgggcagagggccaggcacggctgttggccatttt ttcatgtcggctgctgtgtatcgggtgtgtgggttgattttccgcttcagtatttgagct ctgtgttctgtgaatcgtccgtttttactcacacctaacaaaatgagaatgtgtgcccaa ggaaaatggaacggagcttaacgtacggggaaggaactttcaataaaggaaacatctgat ttccaccacctgggtcagagcatcgggggagggcttgtcagcactgggagtggccaccaa ggagagggggtcatggggcttccgggatggggctgacttgtecttgtttgaactctgacc tecagGACCCCAAAGAGAGGCTCGGCTGCCGGCCACAGACTGGATTTTCTGACATCAAGT
CCCACGCGTTCTTCCGCAGCATAGACTGGGACTTGgtaaagcatcacaaagcctatttgc acccccatccccatcccaaccccaaatctacccaacccccatcccaaccccaaccccaat attcacccaacccccaccccaccccatccgaaccccaatatccatcccaaccccaaattc atccaaccctcaccccaccaccaacccaacccccageccaactcccaccccaacccccaa ctcaacccccaccccaatatccacecaaccccactecaacccctacacccccaacceetc caacccctataatctggtggacagagccggggctgtgtgggectggtgggctgtgtgagc tcgcgcaccgcegggctggtctttgacatggccccacttgcgtggagccaaggctcctgt ctcccagaagggtcagctgggaatgggggaccaccetccagggccccgaggagggatggg gagacacatttcgtcctccggagccaggagagtgaggggccggacgagctcggcccatgg cgcttcctggcaaccctcgactgtgctggcttggtgccgccaggagctageggcacatgc gtcctgacctgtgagcacattggctgttggttccacagggatctgatagtgggggccggc ctagagaagggcgtttgctttggtttcatggccggttttatcagcagttactggacagga ccagcagtcgcagcgttcacggcttgagctttagcgtcgggtattgaaggagagtgagtc tgtggacagggtgcgacgtacactggctcgatttaggaatctgatttcggtggtgtgtga gcagggtgcattcggtagaaactactttgagttttgaccgttccccagctggccgtatga ggtcagtactctcctgtgatgaggggcggtgactgcagccccagcgggccacgtgatcag gagggggccgaatgtcccgaggggctctgcgtgcagggggttttgccggactgtaggctg gcgtgtgtctgtcaggttaaggcaggtaaggctgcgccgcttggtcgtgggttctgtgtg gaagtgcagtctccacccaggatgtttccagcgccgctcggtcgtgggttctgtgtggga agcgcagtctccacctaggatgtttccagcacatggagggtttattgggaggtgaccttg tctgaagctgaggagcgtctgtggaatttgtttccagctgtgtaaatggttgcagagcta__. __, .
ctgaaataaaacctttaaaatacactctcaaggaaaaaagcagattggatagetcgttca gtgcattttggaggaggttgaactgaatcaggagaaagcccagctctagctctgtcctcc accccacccaacttttccaggcagcctcggccagcgtgggaggtcactccctggcccctg tggtcagtgggggcecttgtccacacagcccaacaagtcactttctagtcgaaggccttg ctttgcctgtgcatgtgtgggaccgtgggggaaggtggggagtgaagtggtcagaacgtg cccacaccccttcctacatacagcccttccagagcccagctgggctgctgccaaactagg acggggccattctctgtcgtgcggttgtcagatgcacacacttagaaatgttctgagcat aggcacctgccacggaatcaccttcgcaaattcttcatttaaatttatgcctctggtagc ataagggagaagagatctgectttggttctaactgtcagtcatcctcacgcccaggccgg ggttagaggtggcgtcccttttctctggctcaggcacccetggcctagtggggttactgg tggcgtteccctatctcaggecacacctggcctagctggtgttagtggtggcatccectt gtctctggcccacagaacccctccggtccacacacacactcaggtccaggtaccacccgg ctgaacccgtagcaggtgcttagtagaattacgtgaggagccagcatccccgcteccagc cacctcccctcgcccgtctcagctcagtctcccccgtgcctttcccaccctctctcttcc aagcccaccaccgtatggggcccaccagcaccatgggatccagggagagcecgatcctgg gtgcagccttggtgccagccgggcccctgatcttgtctctcaaccactcttggtttaccg ggagtggacagatgaggacagatggctgcctgtggagtgacgggctccttctcttcggag cactgtctaatctgagtgtgagtccaaccctgeccgagccggaactcaaggagaccatga agccacccttggcetctagctgggagaggtctgcgtccctgcagcgagcacgccaggtga tctctggcacacacttgecgegggctgtctctcggaaggtagtcagcggecctggcttcc cacctgggtcccaccactgcagaatcacccecgtggctgcccacaggggcggcttccatc accctgcttcttcctggctgctgcgggctgtgttgtgacttccatcccagcctgagaggc ctgcgaagggcttgecaccgactgccagecctgcctctgccaccgaccgceggccctgcc tctgccaccgaccgccgaccctgcctctgccgtttccttgccacccatcagctcttgagg cttttaggaagaagtgtggctgttttggecagattgctttagctgtcctcagcagggttg gtgtggggtcaccaccacccccatgtgaccttggcagaaggaaggtectcctcccattca cccaacgcctgcaactcagtggttctgagcaatcccagagttacatgacgtcatcgcgat cactttcatcaccctgtacccagagaagacccgaacecactccagcctctccccacaccc tgcagtggctgctccgccaggctgtgtggctctgcctggtctgcacatgtcatggaagtg gacctgggcacaccgcggcctttcgtgcctgccctcccctcagcattgtctecacaagct gcacccacacagtagcacgtggcactgcctccttcctgcgctgaaccccacccactgcgt ccactgcgtggagactgcacctctgcatccgtcctcagtggacatagggtggcctccact ttetggccattgtgaattgtgctgccgtgaacacetgtgaacccgcttctgggtggactc gtgctgctgtgagcacctgtgaacccgcttctgggtggacacgtgtttatttctcttggg cacgtgctcagggcgcagttgcaggtccggtggtctcagtctagcctttcaggggggcca cctgttcctgcagcggctgctttctggtccctttgggggccccctcagtctgtgctggac ttagttccatggctgtagtgggcacagcttgagaacagtccctcggtgggtgtcagctcc atgtgggagtggggcacgtgtgaggccttggtceccacctgtggactcagggtctctttc acggactgcggggaaggcagtgggagcagcaggaatggatggtgaaaggacacagtgccc gccccccgagtgtccgagggtagagctgggacagggtcacagtcaccccaaagccgcccc ctcettgcctatccccagctgaaccagcaccactcaggcagtcgecgccactggggtgtg actctggggcccggcaccgggtccccaacactgctttcctcctggagcctggcctetgca cactgccctggagaagagaggcagtgtgtgtgcagagggccccgtcagccaggcagatcc acctgccttgcccctgcactgggaggtggcgctcatcttgtcgggggctcccatgggccg tgtctagaccccaccctccgccggtccaggcacatcctcaggctcctaatcctgagtcct ccggtttggctgtgggagcaaaggccgtggggaagttgctgggcctgtcccgggtgagct ttgagtgatggacaggctcattctgaaggaactgggtccagacagcacgtcctggcctgg tggctggggctgccactctaagagggtccccatccccgcaggatccecggtacttggcac actgcaaagcctgagtatttgtggatcacgtgatctgtgctagtgactatcaggagtctg agatttgaagcgatggatttcccagcatggtcccagctccccactgatgtgaaaggtggt ggtgagttaacagctgagccaccacctgctgcccaaccccacgtgtcccacatggccggg cggtgctgcgctaactcatctccccctggatggaaacgtttgcgtggtgacagccgattc tcttgagagtcatttgctgcccatgttgctggggagattctgcctcagggccaggagtgg tttgctcctcccaccccgggcccagggctgctggtgggaggccccagggaggagcaagga ctctaatgcttcgtgtggtgggagcctcaggactttcccacgtgcgacaggcacgttcct gggagctcggtgggaggaacccagccacgttgtgtgctgcgcaaggagccggcggcaggg aggggaaaacggaaagacgcagaggagggcaggtgacaagaggcccacagagagatggct gggtctgggcagcgggtgggagcaggagggaggcggttatgggagacgtggagcagtgga ggccgtcagaagtggggatcacagctgtgacctcatggagagggacaagccccacagctg ggctggtgccagctccactacccagggccaacctgtgtggccgtaaaattctcaagcctg gagtgtgtagaaggcagcagtgccctggcctggccacccgcgaacccctctgtccacccc atgctgcgtggcacagggcaggcgtggggcctctagctggagccttgagtgggtggatcc tcggtggggctttaaggccaacctgtttatgaaaatgcatggggactgactgcagatgca cagacaactcagatgcacagacgcccggacgacgtggacacccagacgatgtggacgcac agacgacatggacgcacagacgatgtggatgcacggacgacgtagacacacggatgactc atccacagatgact~agatgcacggacacccagacgacgcggacgcacagacgacgcgga cgcacagatgacgtggacgcacagatgacgtggacgcacggacgacgtggatgcatggac gacgtggacgcacagatgacctggacgcacggacgacgtggacgcacggatgactcagat ccccagacgactcagatgcacggacacccagatgacatggatgcacggacgactcagatc cacagatgactcaaacgcacagatgactgggatgctcagatgaccgctgctgtgctgcca ccccagggctctctgggcgtttcctgtggtttgggcaccaggagcctgggagtcccatgc tgcccccagggcactacctcctgggcccagccctgcatccggtggcagggctcaccgtca tcaccccaacagtgcagggtggtctcagggacctcctctcatcattgccaagaactggct ccaggatgtttccatgtggccggctagtatggccaaagtggaccctggcgtgctgtcccc ttggacgcctccaggccetgcccagcacgtggggctcgtccatcctgtgcctgaccatgc tctgccatgcggggcctagcccagccccccagccctgctgcttctccccaccccaccccc gccacctccaccaagccaccagcatcctgcctggccctacggacagcagggtcgtcctgt gtccaaaagcctcctccccctcagccccttcactcgggtctcatggggcccctctgtggc ccccagcgcacaaggcacacacccactatggggcctttgcacagctgtgccctccccagg ctccagccctcacctcccccaggctatttctcagatgtcccttcagaactagagcccttg ggcccccagccccattgacacggaacgggcccectgttgtatctcaggtcactgctgtgg ttgcagccacaggggcaacacctgttactgccacagcgtccgacctggggccagcgtgca ttcaaacgcactgctctgagaggccaggacgtccatgggttgggcgcagggggcggcggt gggaaaaggtgtcaggcaccatgggtcccgacctggagcecacgtgccagctgcagagat gggcactgaaggcttttgagcaagaggaggaggtaacgctggcccctggggatgctgtca gggaaactgaggcaatcttgagccctcggagcagagaacgggctgggccaggggctggag gaccctgggccagctccagctgggtcctgctctgttcccacccctgctgcttattaaacc cttgtaaagcagcacaggactaaggtagggaaagtactttaggaaatgCCCCTTTTTCAC
ATTTTATCGGCAGGTGTTTCATACAAAGAATACAAGTAACTGATGAATGAAGGGGGCATC
TTGTGTCCCCACAATCCTGCTGTGCGCACACCACAGGTGAGCCGTTCTGCCTAAGGGAAC
AGCCCCGGCCCCTCCCTCCGGCTCCTCCCCAGCACCGTCTCCTCCACCCAGTGGCCTGGC
CGTGGATGCTGCCTGTGGCCCAGCTTTGAGACACCGCCCTGACACGTGTCCAGCCTTACG
TGGAAGGATTTGTCTGTTTTGTGGCATCCTAGTAGATGCCACGTTAGTAGATGCCATGTT
AGTAGAATGGATGTGGGCATTTCTTTGTAAGTTCCCAAAAGCCTATGAGGGTTTTTTCCA
CGATTCCGTTCCCAGTTTGGCTTTTGTTGTTGTTGTGGCTGTTCTTGGCCCCCCTGGGCC
CTGCAGTGGAGTGGGGGGCTGCACCTGGGAGCCTCGAGCTGAGGCCCAGCCCCTCCTGCC

CTGCATTTTCCTGCCAAGCAGCACCTGAGACTCTGAAGCCGATGCCTATACAGGCAGAAA
CCTGCCAATTCCAGCTTGAACGACTGGAGGGTCCTGAGGATGGGGGTCCCTGGGGTGCCA
TCATGGGCAGGGTGCATCTGTTTGGGTATGCTGCCCCCCAGCTGGCGGGGCACCGGGGAC
AGGCACAGCCACACTGGGGGCATTTCTGGTCTTGGAAGCCTTCTTGGCTCTTCCGGAGGG
AAGGCGGCTGCTGGGTGCCCTGTGATCCACCCGCGAGCTGGGCTGTTCGGCTTGGTCTGC
AGGGGCTGGGGGGCTGCATTTCTTTTCACCAGCTGCACCCACCCGGCCCCATCCTGGCTG
GCACCGAAGGGAGCAGCGCGCCGTGACATCCTCCCCTCAAGCCTGGTGAATGGTGGTTCC
ATGAGGCTGGAGTCAGTGGGTGCCTGTTGTGACAGCTGGATTTCAGTGTTGGTACAGGAG
CACACACCTAAGGGGCGGGCCAGTGAATGAGTGTGCGAGGGTGGGCTAGAGAACGAGCAA
GGGAATGAGAGAGAGTGGGTTAGAGAGTGAGTGAGCCAGTGAATGAGTGAGTGAGCAGGA
GTGGGTTAGAGAGCGAGGGAGTGAGTGAATGAGTGGGCTAAAGAGGGCCGGGCGCGGTGG
CTCACGCCTGTAATCCCAGCACTTTGGGAGGCCGAGGAGGGCAGATGATCTGAGGTCAGC
AGTTCGGGAGCAGCCTGGTCAACATGGTGAAACCCTGCCTCTACTAAAAATACAAAAACA
AAATTAGCCAGGCGTGGTGGCGGGCGCCTGTACTCCCAGCTACTCAGAAGGCTGAGGCGG
GAGAATGGTGTGAACCTGGGAGGTGGAGCTTGCAGTGAGCCGAGATCGTGCCACTGCACT
TCAGCCTGGGAGACAGAGCGAGTCTCAAAACAI~AAACAAAAAACAAAATTAGCTGGGCAT
GGTGGTGCATGCCTGTAGTCCCGGCTACTCAGGAGACTGAGGCAGgagaatagcttgaat cggagtcagaggttgcagtgagccgagatcgcgccactgcactccagcctgggcaacaga gcaagactccatctcaaaaaaaaagtgggctagagagtgagtgagtgaatgagtgaatgg gagtgggttagcgagggagtgagagggtgaatgggagtgggttagagagggagtgagagg gtgaatgggagtgggttagagagtgagggagtaagcgagtgaatgtctcttggtgctgct gtaacagaatacctgagcgagcctgggtaatttctagggagcagagttctttcccagctg tggaggttgggagtecagggtcatggtgccagcaggcttggtgtctggtgaggcctgatc tctgcttccaagatggegcccaaacactgcattccccggaggagagaggggaggaaggcc acgtgtccacatggcagaaggcagagaggaatccatgcccaagctgtcttgacagctaca ggagtttgtctgtgagggcggggctcccatcaggttecacctctctacactgttgctctg gggaatgagtttctcactgtgaatctggggggcacattcagaccctattgtgggtgagtg ggagagcatggctgtgtcactgggacaagtggccatgagtcgggggaactgaggggtttt cagtgtcctcacccgtatgtgttgtggcacctgtgccaggcaccagcgttctgccctccc cggcacaggcgcatcaccgagtcccaggcccgcctgctgggcattttcctgccaagcagc acctgagattctgaagtcgatgcctggataggcagaaatgggecggcaggaggctcctga cagacgggtctgtgcagtgccagcgcaggcagggtgctgtggccaggtcctacaccttta tggtcagggttccaagacgtcatgagacggcttgttcagccagttagttgtcggtgcccc tctgaacaaggacccccccaaggaagggggtggcctcgcatgggtggctggggatcctgc tccgtcccacatgtggccagcatggccgacactggcatttctcagctcgacaacaatttt tctgactttggatattttctagattttgtgttgtaagaaaaaacacttggcagtcaaata ctaggcagattgaaatgctgactttctcactgtttcattttgtgattgaagtgcgtgcaa aacactcaatctggtagggatgatgeccgcgcggagctgacccttctcctattgtttttc caagCTGGAGAAGAAGCAGGCGCTCCCTCCATTCCAGCCACAGATCACAGACGACTACGG
TCTGGACAACTTTGACACACAGTTCACCAGCGAGCCCGTGCAGCTGACCCCAGACGATGA
gtgagtcccactgggtgcgggtccctggagcacccctcgggcagccccatggcaggccgg caccttgggcagctggtgacccagcctgcccttgagtcccacccgcctggtgtcatctct ccagtgggcgttgggggaggattcttatgcgaacgtgactccgcttcccccaagggaatg aacacacggtcacccccctcccccctgccacctttgeccacagGGATGCCATAAAGAGGA
TCGACCAGTCAGAGTTCGAAGGCTTTGAGTATATCAACCCATTATTGCTGTCCACCGAGG
AGTCGGTGTGAGGCCGCGTGCGTCTCTGTCGTGGACACGCGTGATTGACCCTTTAACTGT
ATCCTTAACCACCGCATATGCATGCCAGGCTGGGCACGGCTCCGAGGGCGGCCAGGGACA
GACGCTTGCGCCGAGACCGCAGAGGGAAGCGTCAGCGGGCGCTGCTGGGAGCAGAACAGT
CCCTCACACCTGGGCCCGGGCAGGCCAGCTTCGTGCTGGAGGAACTTGCTGCTGTGCCTG
CGTCGCGGCGGATCCGCGGGGACCCTGCCGAGGGGGCTGTCATGCGGTTTCCAAGGTGCA
CATTTTCCACGGAAACAGAACTCGATGCACTGACCTGCTCCGCCAGGAAAGTGAGCGTGT
AGCGTCCTGAGGAATAAAATGTTCCGATGA
SEQ ID NO: ~ non-conventional ATP binding site motif, wherein G is amino acid glycine, X is any amino acid GXGXXA
SEQ ID NO: 9 ATP binding site hallmark motif, wherein G is amino acid glycine, X

is any amino acid GXGXXG
SEQ ID NO: 10 A zeta-inhibitory peptide (ZIP): myristoylated PKC~
pseudosubstrate peptide SIYRRGARRWRKLY
SEQ ID NO: 11 Human PKC zeta I amino acid sequence MPSRTGPKMEGSGGRVRLKAHYGGDIFITSVDAATTFEELCEEVRDMCRLH
QQHPLTLKWVDSEGDPCTVSSQMELEEAFRLARQCRDEGLIIHVFPSTPEQP
GLPCPGEDKSIYRRGARRWRKLYRANGHLFQAKRFNRRAYCGQCSERIWG
LARQGYRCINCKLLVHKRCHGLVPLTCRKHMDSVMPSQEPPVDDKNEDAD
LPSEETDGIAYISSSRKHDSIKDDSEDLKPVIDGMDGIKISQGLGLQDFDLIRVI
GRGSYAKVLLVRLKKNDQIYAMKV VKKELVHDDEDIDW V QTEKHVFEQA
SSNPFLVGLHSCFQTTSRLFLVIEYVNGGDLMFHMQRQRKLPEEHARFYAA
EICIALNFLHERGIIYRDLKLDNVLLDADGHIKLTDYGMCKEGLGPGDTTSTF
CGTPNYIAPEILRGEEYGFSVDWWALGVLMFEMMAGRSPFDIITDNPDMNT
EDYLFQVILEKPIRIPRFLSVKASHVLKGFLNKDPKERLGCRPQTGFSDIKSH
AFFRSIDWDLLEKKQALPPFQPQITDDYGLDNFDTQFTSEPVQLTPDDEDAIK

SEQ ID NO: 12 CCATGCCCAGCAGGACCACC
SEQ ID NO: 13 CCTTCTATTAGATGCCTGCTCTCC
SEQ ID NO: 14 TGAAGGAAGGTCTACACCATCGTTC
SEQ ID NO: 15 ACATGGTCTACATGTTCC
SEQ ID NO: 16 CAGATCCACAACGGAATAC

Claims (37)

WHAT IS CLAIMED IS:

1. A method for diagnosing a nervous system disorder in a subject comprising:
a. contacting a sample from said subject with an aPKC specific probe, b. detecting the binding of said probe to said sample to determine the activity of said aPKC in said sample, c. contacting a control sample with said aPKC specific probe,~
d. detecting the binding of said probe to said control sample to~
determine the activity of said aPKC in said control sample, and e. comparing the activity of said aPKC in Step b with the activity of said aPKC in Step d, wherein if the activity of said aPKC in Step b is different from the activity of said aPKC in Step d, a nervous system disorder in said subject is present.

2. The method of Claim 1, wherein Step d is performed by quantifying a label attached to said probe.

3. The method of Claim 1, wherein said disorder is a neurodegenerative, neurological or psychiatric disorder.

4. The method of Claim 1, wherein said probe is an antibody or a nucleic acid sequence.

5. The method of Clam 1, wherein said sample is a human tissue or tissue extract or body fluid.

6. The method of Clam 5, wherein said tissue is postmortem autopsy tissue or brain biopsy tissue.

7. The method of Claim 1, wherein said nervous system disorder is selected from the group consisting of Alzheimers disease (AD), Pick's disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Parkinson's disease (PD) and multisystem atrophy (MSA).

8. A method for identifying a compound useful for modulating the activity of an aPKC comprising:
a. providing cells wherein said aPKC gene is expressed, b. incubating said cells with a candidate compound for a sufficient time to induce a change in the activity of aPKC in said cells, c. incubating said cells as in Step b, in the absence of said candidate compound or in the presence of a control compound, d. ~contacting said cells from Step b and Step c with an equal amount of an Akka-specific probe, e. ~detecting the binding of said probe to said cells to determine the activity of said Akka in said cell from Step b and Step c, and f. ~comparing the activity of said Akka in said cells, wherein if the activity of said Akka in said cells from Step b is different from the activity of said Akka in said cells from Step c, said candidate compound modulates Akka.

9. ~The method of Claim 8, wherein said compound is a peptide, a small molecule or a macromolecule.

10. An in vitro method for identifying a compound useful for modulating the activity of an Akka comprising:
a. ~providing cells wherein Akka gene is expressed, b. ~incubating an Akka in a first container with adenosine triphosphate (ATP), a substrate of said Akka and a candidate compound, wherein the phosphate of said ATP is radioactively labeled, for a sufficient time to induce a change in the activity of Akka in said cells, c. ~incubating said Akka in a second container with ATP and said substrate of said Akka, wherein the phosphate of said ATP is radioactively labeled, for a sufficient time to induce a change in the activity of Akka in said cells d. ~quantifying the amount of incorporation of the radioactively-labeled phosphate into said substrate in said first container and said second container, e. ~comparing the amount of incorporation in said first container and said second container, whereby a difference in the amount of incorporation in said first container and said second container inindicates that said candidate compound is identified as a compound modulating Akka activity.

11. The method of Claim 10, wherein said substrate is a protein tau or GSK3.beta..

12. A method for treating a nervous system disorder in a subject comprising:
a. ~inserting an Akka sequence into an expression vector, and b. ~administering said vector from Step a to said subject.

13. A method for preventing a nervous system disorder in a subject, comprising:
a. inserting the aPKC sequence into an expression vector, and b. administering said vector from Step a to said subject.

14. The method of Claims 12-13, wherein said expression vector is administered via intraventricular, intravenous, inhalation, dermal or oral route.

15. The method of Claims 12-13, wherein the dosage to be administered is sufficient to maintain said aPKC activity at a normal level.

16. The method of Claim 15, wherein said normal level is an amount of said aPKC from about 0.005% to about 0.05% of total protein in a sample from said subject.

17. The method of Claim 13, wherein said method comprises gene therapy.

18. The method of any of the Claims 1, 13-14, wherein said disorder is characterized by abnormal aPKC activity.

19. The method of Claim 18, wherein said abnormal aPKC activity comprises phosphorylation of protein tau and co-localization with neurofibrillary tangles (NFT).

20. The method of any one of Claims 1, 13-14, wherein said disorder is selected from the group consisting of Alzheimer's disease (AD), Pick's disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Parkinson's disease (PD) and multisystem atrophy (MSA).

21. A method of any one of Claims 1-19, wherein said aPKC is PKM.zeta..

22. An antibody which binds to an isoform of an aPKC molecule or a functional derivative thereof.

23. The antibody of Claim 22, wherein said aPKC is PKM.zeta.

24. A method for treating a nervous system disorder of a subject comprising:
a. generating an antibody against PKM.zeta., and b. administering said antibody or a functional fragment thereof to said subject.

25. A method for constructing an animal model of neurological dysfunction comprising:
a. constructing a transgenic animal having an altered aPKC amount, localization or activity, b. treating said transgenic animal from Step a with a candidate compound c. treating said transgenic animal from Step a with a control compound, d. assaying said transgenic animals from Steps b and c for a biochemical or behavioral changes, and e. comparing the results from Step d, wherein differences are indicative the efficacy of said candidate compound in treatment of said neurological dysfunction.

26. ~The method of Claim 25, wherein said transgenic animal is a knock-out mouse lacking aPKC.

27. ~The method of Claim 25, wherein said transgenic animal is a mouse that overexpresses an aPKC.

28. ~The method of any of Claims 25-27, wherein said aPKC is a wild type or mutant aPKC

29. ~The method of Claim 25, wherein said biochemical change is tau phosphorylation

30. ~The method of Claim 25, wherein said behavioral change is a memory deficit.

31. ~A method for screening DNA for a mutation or polymorphisms in the DNA
sequence of the aPKC genes and regions regulating the expression of these genes comprising:
a. ~isolating DNA from a sample of a subject, b. ~sequencing said DNA, and c. ~comparing said sequence to a reference DNA sequence, whereby a difference between the DNA sequence derived from said subject and the reference sequence is indicative of genetic susceptibility to a neurological or psychiatric disorder.

32. ~The method of Claim 31, wherein Step c is performed by comparing single nucleotide polymorphisams (SNPs) on said sequence to SNPs on said reference DNA sequence.

33. ~The method of Claim 31, wherein said reference DNA sequence is a human genomic sequence of PKC iota/lambada set forth in SEQ ID NO: 6.

34. ~The method of Claim 31, wherein said reference DNA sequence is a human genomic sequence of PKC zeta set forth in SEQ ID NO: 7.

35. A method for diagnosing cancer comprising:
a. contacting a tumor sample from a subject with an aPKC specific probe, b. detecting the binding of said probe to said tumor sample to quantify the activity of said aPKC in said tumor sample, c. contacting a control sample with said aPKC specific probe, d. detecting the binding of said probe to said control sample to quantify the activity of said aPKC in said control sample, and e. comparing said activity of said aPKC in Step b with said activity of said aPKC in Step d, wherein the difference of the activity of said aPKC is indicative of the type or the staging of said cancer.

36. The method of Claim 35, wherein said cancer is selected from the group consisting of neuroblastoma, oligodendroglioma, meningioma, lymphoma (myeloma), leukemia, melanoma, squamous cell carcinoma, hepatocellular carcinoma, parathyroid tumors, pheochromocytoma, paraganglioma, intravascular lymphomatosis, breast cancer, liver cancer, lung cancer, prostate cancer, bladder cancer, ovarian cancer, endometrial cancer, head and neck cancer, colorectal cancer and pancreatic cancer.

37. The method of Claims 35-36, wherein said method comprises gene therapy.