DIAGNOSTIC GENE MARKER PANEL FOR COLORECTAL CANCER

Abstract

The present invention relates generally to a method of screening for the onset, predisposition to the onset and/or progression of a neoplasm. More particularly, the present invention relates to a method of screening for the onset, predisposition to the onset and/or progression of a neoplasm by screening for changes to the methylation levels of a panel of gene markers. The method of the present invention is useful in a range of applications including, but not limited to, those relating to the diagnosis and/or monitoring of colorectal neoplasms, such as colorectal adenocarcinosis.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation application of U.S. application Ser. No. 14/400,313, filed Nov. 10, 2014, which is a U.S. National Phase Application of PCT International Application Number PCT/AU2013/000481, filed May 10, 2013, designating the United States of America and published in the English language, which is an International Application of and claims the benefit of priority to U.S. Provisional Application No. 61/646,174, filed May 11, 2012, the disclosures of which are hereby expressly incorporated by reference in their entireties.

REFERENCE TO SEQUENCE LISTING

[0002] A Sequence Listing submitted as an ASCII text file via EFS-Web is hereby incorporated by reference in accordance with 35 U.S.C. .sctn. 1.52(e).

FIELD

[0003] The present invention relates generally to a method of screening for the onset, predisposition to the onset and/or progression of a neoplasm. More particularly, the present invention relates to a method of screening for the onset, predisposition to the onset and/or progression of a neoplasm by screening for changes to the methylation levels of a panel of gene markers. The method of the present invention is useful in a range of applications including, but not limited to, those relating to the diagnosis and/or monitoring of colorectal neoplasms, such as colorectal adenocarcinosis.

BACKGROUND

[0004] Colorectal cancer includes cancerous growths in the colon, rectum and appendix. With 655,000 deaths worldwide per year, it is the fourth most common form of cancer in the United States and the third leading cause of cancer-related death in the Western world. Colorectal cancers arise from adenomatous polyps in the colon. These mushroom-shaped growths are usually benign, but some develop into cancer over time. Localized colon cancer is usually diagnosed through colonoscopy.

[0005] Invasive cancers that are confined within the wall of the colon (stages I and II) are curable with surgery. If untreated, they spread to regional lymph nodes (stage III), where up to 73% are curable by surgery and chemotherapy. Cancer that metastasizes to distant sites (stage IV) is usually not curable, although chemotherapy can extend survival, and in rare cases, surgery and chemotherapy together have seen patients through to a cure (Markowitz and Bertagnolli, 2009, N. Engl. J. Med. 361(25): 2449-60). Radiation is used with rectal cancer.

[0006] Colorectal cancer is preceded by adenomas. Adenomas are benign tumors, or neoplasms, of epithelial origin which are derived from glandular tissue or exhibit clearly defined glandular structures. Some adenomas show recognizable tissue elements, such as fibrous tissue (fibroadenomas) and epithelial structure, while others, such as bronchial adenomas, produce active compounds that might give rise to clinical syndromes.

[0007] Adenomas may progress to become an invasive neoplasm and are then termed adenocarcinomas. Accordingly, adenocarcinomas are defined as malignant epithelial tumors arising from glandular structures, which are constituent parts of many organs of the body. The term adenocarcinoma is also applied to tumors showing a glandular growth pattern. These tumors may be sub-classified according to the substances that they produce, for example mucus secreting and serous adenocarcinomas, or to the microscopic arrangement of their cells into patterns, for example papillary and follicular adenocarcinomas. These carcinomas may be solid or cystic (cystadenocarcinomas). Each organ may produce tumors showing a variety of histological types, for example the ovary may produce both mucinous and cystadenocarcinoma.

[0008] Adenomas in different organs behave differently. In general, the overall chance of carcinoma being present within an adenoma (i.e. a focus of cancer having developed within a benign lesion) is approximately 5%. However, this is related to size of an adenoma. For instance, in the large bowel (colon and rectum specifically) occurrence of a cancer within an adenoma is rare in adenomas of less than 1 centimeter. Such a development is estimated at 40 to 50% in adenomas which are greater than 4 centimeters and show certain histopathological change such as villous change, or high-grade dysplasia. Adenomas with higher degrees of dysplasia have a higher incidence of carcinoma. In any given colorectal adenoma, the predictors of the presence of cancer now or the future occurrence of cancer in the organ include size (especially greater than 9mm) degree of change from tubular to villous morphology, presence of high-grade dysplasia and the morphological change described as "serrated adenoma". In any given individual, the additional features of increasing age, familial occurrence of colorectal adenoma or cancer, male gender or multiplicity of adenomas, predict a future increased risk for cancer in the organ--so-called risk factors for cancer. Except for the presence of adenomas and its size, none of these is objectively defined and all those other than number and size are subject to observer error and to confusion as to precise definition of the feature in question. Because such factors can be difficult to assess and define, their value as predictors of current or future risk for cancer is imprecise.

[0009] Once a sporadic adenoma has developed, the chance of a new adenoma occurring is approximately 30% within 26 months.

[0010] The symptoms of colorectal cancer depend on the location of tumor in the bowel, and whether it has metastasized. Unfortunately, many of the symptoms may occur in other diseases as well, and hence symptoms may not be conclusively diagnostic of colorectal cancer.

[0011] Local symptoms are more likely if the tumor is located closer to the anus. There may be a change in bowel habit (new-onset constipation or diarrhea in the absence of another cause), a feeling of incomplete defecation and reduction in diameter of stools. Tenesmus and change in stool shape are both characteristic of rectal cancer. Lower gastrointestinal bleeding, including the passage of bright red blood in the stool, may indicate colorectal cancer, as may the increased presence of mucus. Melena, black stool with a tarry appearance, normally occurs in upper gastrointestinal bleeding (such as from a duodenal ulcer), but is sometimes encountered in colorectal cancer when the disease is located in the beginning of the large bowl.

[0012] A tumor that is large enough to fill the entire lumen of the bowel may cause bowel obstruction. This situation is characterized by constipation, abdominal pain, abdominal distension and vomiting. This occasionally leads to the obstructed and distended bowel perforating and causing peritonitis.

[0013] Certain local effects of colorectal cancer occur when the disease has become more advanced. A large tumor is more likely to be noticed on feeling the abdomen, and it may be noticed by a doctor on physical examination. The disease may invade other organs, and may cause blood or air in the urine or vaginal discharge.

[0014] If a tumor has caused chronic occult bleeding, iron deficiency anemia may occur. This may be experienced as fatigue, palpitations and noticed as pallor. Colorectal cancer may also lead to weight loss, generally due to a decreased appetite.

[0015] More unusual constitutional symptoms are an unexplained fever and one of several paraneoplastic syndromes. The most common paraneoplastic syndrome is thrombosis, usually deep vein thrombosis.

[0016] Colorectal cancer most commonly spreads to the liver. This may go unnoticed, but large deposits in the liver may cause jaundice and abdominal pain (due to stretching of the capsule). If the tumor deposit obstructs the bile duct, the jaundice may be accompanied by other features of biliary obstruction, such as pale stools.

[0017] Colorectal cancer can take many years to develop and early detection of colorectal cancer greatly improves the prognosis. Even modest efforts to implement colorectal cancer screening methods can result in a drop in cancer deaths. Despite this, colorectal cancer screening rates remain low. There are currently several different tests available for this purpose:

[0018] Digital rectal exam: The doctor inserts a lubricated, gloved finger into the rectum to feel for abnormal areas. It only detects tumors large enough to be felt in the distal part of the rectum but is useful as an initial screening test.

[0019] Fecal occult blood test: a test for blood in the stool. Two types of tests can be used for detecting occult blood in stools i.e. guaiac based (chemical test) and immunochemical. The sensitivity of immunochemical testing is superior to that of chemical testing without an unacceptable reduction in specificity (Weitzel J N (December 1999). "Genetic cancer risk assessment. Putting it all together". Cancer 86 (11 Suppl): 2483-92).

[0020] Endoscopy:

[0021] Sigmoidoscopy: A lit probe (sigmoidoscope) is inserted into the rectum and lower colon to check for polyps and other abnormalities.

[0022] Colonoscopy: A lit probe called a colonoscope is inserted into the rectum and the entire colon to look for polyps and other abnormalities that may be caused by cancer. A colonoscopy has the advantage that if polyps are found during the procedure they can be removed immediately. Tissue can also be taken for biopsy.

[0023] Double contrast barium enema (DCBE): First, an overnight preparation is taken to cleanse the colon. An enema containing barium sulfate is administered, then air is insufflated into the colon, distending it. The result is a thin layer of barium over the inner lining of the colon which is visible on X-ray films. A cancer or a precancerous polyp can be detected this way. This technique can miss the (less common) flat polyp.

[0024] Virtual colonoscopy replaces X-ray films in the double contrast barium enema (above) with a special computed tomography scan and requires special workstation software in order for the radiologist to interpret. This technique is approaching colonoscopy in sensitivity for polyps. However, any polyps found must still be removed by standard colonoscopy.

[0025] Standard computed axial tomography is an x-ray method that can be used to determine the degree of spread of cancer, but is not sensitive enough to use for screening. Some cancers are found in CAT scans performed for other reasons.

[0026] Blood tests: Measurement of the patient's blood for elevated levels of certain proteins can give an indication of tumor load. In particular, high levels of carcinoembryonic antigen (CEA) in the blood can indicate metastasis of adenocarcinoma. While these tests are frequently false positive or false negative, and are not recommended for screening, they can be useful to assess disease recurrence. CA19-9 and CA 242 biomarkers can indicate e-selectin related metastatic risks, help follow therapeutic progress, and assess disease recurrence. Recently, an assay for detection in plasma of methylated sequences of the Septin 9 gene has also become available to assist in diagnosis of colorectal cancer.

[0027] Positron emission tomography (PET) is a 3-dimensional scanning technology where a radioactive sugar is injected into the patient, the sugar collects in tissues with high metabolic activity, and an image is formed by measuring the emission of radiation from the sugar. Because cancer cells often have very high metabolic rates, this can be used to differentiate benign and malignant tumors. PET is not used for screening and does not (yet) have a place in routine workup of colorectal cancer cases.

[0028] Stool DNA testing is an emerging technology in screening for colorectal cancer. Premalignant adenomas and cancers shed DNA markers from their cells which are not degraded during the digestive process and remain stable in the stool. Capture, followed by PCR amplifies the DNA to detectable levels for assay.

[0029] High C-Reactive Protein Levels as Risk Marker

[0030] Despite the existence of these tests, diagnosis remains problematic. Most of the more sensitive tests are quite invasive and expensive and therefore uptake by patients is low. There is therefore an ongoing need to develop simpler and more informative diagnostic protocols or aids to diagnosis that enable one to direct colonoscopy at people more likely to have developed adenomas or carcinomas. A simple and accurate screening test would enable much more widely applicable screening systems to be set up.

[0031] To this end, more recently there have been identified genetic markers which are modulated, in terms of their expression levels, in individuals who have developed a neoplasm of the large intestine. Some of these markers are upregulated in terms of their level of expression, while others are downregulated. However, a feature common to most of these markers, and the use of genetic marker expression levels in general as a diagnostic, is that they often exhibit only moderate levels of sensitivity and specificity. The development of diagnostic protocols which provide high levels of sensitivity and specificity is highly sought after.

[0032] In work leading up to the present invention, it has been unexpectedly determined that the gene markers BCAT1, IKZF1 IRF4, GRASP and CAHM, although each individually being one of a number of gene markers known to exhibit utility in terms of diagnosing colorectal neoplasia development, have in fact been determined to collectively enable a significantly higher level of sensitivity or specificity to be achieved than where any one of these gene markers is analyzed either alone or together with other unrelated gene markers. More specifically, screening for an increase in the level of methylation of any two or more of these five specific markers can be designed so as to achieve a level of specificity or sensitivity not previously achievable.

[0033] Bearing in mind the large number of gene markers which, in differential gene expression analysis studies, have been shown to exhibit modulated expression levels in neoplasia, the identification that five specific markers can in fact collectively provide improved diagnostic outcomes relative either to these markers individually or to other groups of markers is both unexpected and unpredictable.

SUMMARY

[0034] Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

[0035] As used herein, the term "derived from" shall be taken to indicate that a particular integer or group of integers has originated from the species specified, but has not necessarily been obtained directly from the specified source. Further, as used herein the singular forms of "a", "and" and "the" include plural referents unless the context clearly dictates otherwise.

[0036] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0037] The subject specification contains nucleotide sequence information prepared using the program PatentIn Version 3.5, presented herein after the bibliography. Each nucleotide sequence is identified in the sequence listing by the numeric indicator <210> followed by the sequence identifier (e.g. <210>1, <210>2, etc.). The length, type of sequence (DNA, etc.) and source organism for each sequence is indicated by information provided in the numeric indicator fields <211>, <212> and <213>, respectively. Nucleotide sequences referred to in the specification are identified by the indicator SEQ ID NO: followed by the sequence identifier (e.g. SEQ ID NO:1, SEQ ID NO:2, etc.). The sequence identifier referred to in the specification correlates to the information provided in numeric indicator field <400> in the sequence listing, which is followed by the sequence identifier (e.g. <400>1, <400>2, etc.). That is SEQ ID NO:1 as detailed in the specification correlates to the sequence indicated as <400>1 in the sequence listing.

[0038] One aspect of the present invention is directed to a method of screening for the onset or predisposition to the onset of or monitoring a large intestine neoplasm in an individual, said method comprising assessing the methylation status of a DNA region selected from:

[0039] (i) the region, including 2 kb upstream of the transcription start site, defined by any two or more of Hg19 coordinates:

[0040] (1) chr12:24962958..25102393

[0041] (2) chr7:50344378...50472798

[0042] (3) chr6:391739..411443;

[0043] (4) chr12:52400748..52409671; and

[0044] (5) chr6:163834097..163834982; or

[0045] (ii) the gene region, including 2 kb upstream of any two or more of:

[0046] (1) BCAT1 (2) IKZF1 (3) IRF4 (4) GRASP and (5) CAHM in a biological sample from said individual wherein a higher level of methylation of at least one of the DNA regions of group (i) and/or (ii) relative to control levels is indicative of a large intestine neoplasm or a predisposition to the onset of a large intestine neoplastic state.

[0047] In another aspect said method is directed to identifying biological samples in which any one of said DNA regions exhibits a higher level of methylation.

[0048] In still another aspect said method is directed to identifying biological samples in which two or more of said DNA regions exhibit a higher level of methylation.

[0049] In yet another aspect there is provided a method of screening for the onset or predisposition to the onset of or monitoring a large intestine neoplasm in an individual, said method comprising assessing the methylation status of:

[0050] the DNA regions, including 2 kb upstream of the transcription start site, defined by Hg19 coordinates:

[0051] (1) chr12:24962958..25102393; and

[0052] (2) chr7:50344378...50472798;

[0053] and optionally one or more of (3) chr6:391739..411443, (4) chr12:52400748..52409671 and (5) chr6:163834097..163834982; or

[0054] (ii) the gene region, including 2 kb upstream of:

[0055] (1) BCAT1; and

[0056] (2) IKZF1;

[0057] and optionally one or more of (3) IRF4, (4) GRASP and (5) CAHM in a biological sample from said individual wherein a higher level of methylation of at least one of the DNA regions of group (i) and/or (ii) relative to control levels is indicative of a large intestine neoplasm or a predisposition to the onset of a large intestine neoplastic state.

[0058] In one embodiment of this aspect, the gene marker panel which is screened for is:

[0059] (i) the DNA regions, including 2 kb upstream of the transcription start site, defined by Hg19 coordinates:

[0060] (1) chr12:24962958..25102393

[0061] (2) chr7:50344378...50472798; and

[0062] (3) chr6:391739..411443; or

[0063] (ii) the gene region, including 2 kb upstream of:

[0064] (1) BCAT1, (2) IKZFI and (3) IRF4.

[0065] In another embodiment of this aspect, the gene marker panel which is screened for is:

[0066] (i) the DNA regions, including 2 kb upstream of the transcription start site, defined by Hg19 coordinates:

[0067] (1) chr12:24962958..25102393

[0068] (2) chr7:50344378...50472798 and

[0069] (4) chr12:52400748..52409671; or

[0070] (ii) the gene region, including 2 kb upstream of:

[0071] (1) BCAT1, (2) IKZFI; and (4) GRASP.

[0072] In still another embodiment of this aspect, the gene marker panel which is screened for is:

[0073] (i) the DNA regions, including 2 kb upstream of the transcription start site, defined by Hg19 coordinates:

[0074] (1) chr12:24962958..25102393

[0075] (2) chr7:50344378...50472798 and

[0076] (5) chr6:163834097..163834982; or

[0077] (ii) the gene region, including 2 kb upstream of:

[0078] (1) BCATI, (2) 1KZF1 and (5) CAHM

[0079] In still yet another embodiment of this aspect, the gene marker panel which is screened for is:

[0080] (i) the DNA regions, including 2 kb upstream of the transcription start site, defined by Hg19 coordinates:

[0081] (1) chr12:24962958..25102393

[0082] (2) chr7:50344378...50472798

[0083] (3) chr6:391739..411443; and

[0084] (4) chr12:52400748..52409671; or

[0085] (ii) the gene region, including 2 kb upstream of:

[0086] (1) BCAT1, (2) IKZF1, (3) IRF4 and (4) GRASP.

[0087] In yet still another embodiment of this aspect, the gene marker panel which is screened for is:

[0088] (i) the DNA regions, including 2 kb upstream of the transcription start site, defined by Hg19 coordinates:

[0089] (1) chr12:24962958..25102393

[0090] (2) chr7:50344378...50472798

[0091] (3) chr6:391739..411443; and

[0092] (5) chr6:163834097..163834982; or

[0093] (ii) the gene region, including 2 kb upstream of:

[0094] (1) BCAT1, (2) IKZF1, (3) IRF4 and (5) CAHM

[0095] In a further embodiment of this aspect, the gene marker panel which is screened for is:

[0096] (i) the DNA regions, including 2 kb upstream of the transcription start site, defined by Hg19 coordinates:

[0097] (1) chr12:24962958..25102393

[0098] (2) chr7:50344378...50472798

[0099] (4) chr12:52400748..52409671 and

[0100] (5) chr6:163834097..163834982; or

[0101] (ii) the gene region, including 2 kb upstream of:

[0102] (1) BCAT1, (2) 1KZF1, (4) GRASP and (5) CAHM

[0103] In yet another further embodiment of this aspect, the gene marker panel which is screened for is:

[0104] (i) the DNA regions, including 2 kb upstream of the transcription start site, defined by Hg19 coordinates:

[0105] (1) chr12:24962958..25102393

[0106] (2) chr7:50344378...50472798

[0107] (3) chr6:391739..411443

[0108] (4) chr12:52400748..52409671 and

[0109] (5) chr6:163834097..163834982; or

[0110] (ii) the gene region, including 2 kb upstream of:

[0111] (1) BCAT1, (2) IKZF1, (3) IRF4, (4) GRASP and (5) CAHM.

[0112] In another embodiment there is provided a method of screening for the onset or predisposition to the onset of or monitoring a large intestine neoplasm in an individual, said method comprising assessing the methylation status of:

[0113] (i) the DNA regions, including 2 kb upstream of the transcription start site, defined by Hg19 coordinates:

[0114] (1) chr12:24962958..25102393; and

[0115] (5) chr6:163834097..163834982;

[0116] and optionally one or more of (2) chr7:50344378...50472798, (3) chr6:391739..411443; and (4) chr12:52400748..52409671; or

[0117] (ii) the gene region, including 2 kb upstream of:

[0118] (1) BCAT1; and

[0119] (5) CAHM;

[0120] and optionally one or more of (2) IKZF1, (3) IRF4 and (4) GRASP in a biological sample from said individual wherein a higher level of methylation of at least one of the DNA regions of group (i) and/or (ii) relative to control levels is indicative of a large intestine neoplasm or a predisposition to the onset of a large intestine neoplastic state.

[0121] In still another embodiment there is provided a method of screening for the onset or predisposition to the onset of or monitoring a large intestine neoplasm in an individual, said method comprising assessing the methylation status of:

[0122] (i) the DNA regions, including 2 kb upstream of the transcription start site, defined by Hg19 coordinates:

[0123] (2) chr7:50344378..50472798; and

[0124] (5) chr6:163834097..163834982;

[0125] and optionally one or more of (1) chr12:24962958..25102393, (3) chr6:391739..411443 and (4) chr12:52400748..52409671; or

[0126] (ii) the gene region, including 2 kb upstream of:

[0127] (2) IKZF 1; and

[0128] (5) CAHM;

[0129] and optionally one or more of (1) BCAT1, (3) IRF4 and (4) GRASP in a biological sample from said individual wherein a higher level of methylation of at least one of the DNA regions of group (i) and/or (ii) relative to control levels is indicative of a large intestine neoplasm or a predisposition to the onset of a large intestine neoplastic state.

[0130] In a further embodiment there is provided a method of screening for the onset or predisposition to the onset of or monitoring a large intestine neoplasm in an individual, said method comprising assessing the methylation status of:

[0131] (i) the DNA regions, including 2 kb upstream of the transcription start site, defined by Hg19 coordinates:

[0132] (1) chr12:24962958..25102393; and

[0133] (3) chr6:391739..411443;

[0134] and optionally one or more of (2) chr7:50344378...50472798, (4) chr12:52400748..52409671 and (5) chr6:163834097..163834982; or

[0135] (ii) the gene region, including 2 kb upstream of:

[0136] (1) BCAT1; and

[0137] (3) IRF4;

[0138] and optionally one or more of (2) IKZF 1, (4) GRASP and (5) CAHM in a biological sample from said individual wherein a higher level of methylation of at least one of the DNA regions of group (i) and/or (ii) relative to control levels is indicative of a large intestine neoplasm or a predisposition to the onset of a large intestine neoplastic state.

[0139] In yet another further embodiment there is provided a method of screening for the onset or predisposition to the onset of or monitoring a large intestine neoplasm in an individual, said method comprising assessing the methylation status of:

[0140] (i) the DNA regions, including 2 kb upstream of the transcription start site, defined by Hg19 coordinates:

[0141] (1) chr12:24962958..25102393; and

[0142] (4) chr12:52400748..52409671;

[0143] and optionally one or more of (2) chr7:50344378...50472798, (3) chr6:391739..411443 and (5) chr6:163834097..163834982; or

[0144] (ii) the gene region, including 2 kb upstream of:

[0145] (1) BCAT1; and

[0146] (4) GRASP;

[0147] and optionally one or more of (2) IKZF1, (3) IRF4 and (5) CAHM in a biological sample from said individual wherein a higher level of methylation of at least one of the DNA regions of group (i) and/or (ii) relative to control levels is indicative of a large intestine neoplasm or a predisposition to the onset of a large intestine neoplastic state.

[0148] In still another further embodiment there is provided a method of screening for the onset or predisposition to the onset of or monitoring a large intestine neoplasm in an individual, said method comprising assessing the methylation status of:

[0149] (i) the DNA regions, including 2 kb upstream of the transcription start site, defined by Hg19 coordinates:

[0150] (2) chr7:50344378..50472798; and

[0151] (3) chr6:391739..411443;

[0152] and optionally one or more of (1) chr12:24962958..25102393, (4) chr12:52400748..52409671 and (5) chr6:163834097..163834982; or

[0153] (ii) the gene region, including 2 kb upstream of:

[0154] (2) IKZF 1; and

[0155] (3) IRF4;

[0156] and optionally one or more of (1) BCAT1, (4) GRASP and (5) CAHM in a biological sample from said individual wherein a higher level of methylation of at least one of the DNA regions of group (i) and/or (ii) relative to control levels is indicative of a large intestine neoplasm or a predisposition to the onset of a large intestine neoplastic state.

[0157] In yet still another embodiment there is provided a method of screening for the onset or predisposition to the onset of or monitoring a large intestine neoplasm in an individual, said method comprising assessing the methylation status of:

[0158] (i) the DNA regions, including 2 kb upstream of the transcription start site, defined by Hg19 coordinates:

[0159] (2) chr7:50344378..50472798; and

[0160] (4) chr12:52400748..52409671;

[0161] and optionally one or more of (1) chr12:24962958..25102393, (3) chr6:391739..411443 and (5) chr6:163834097..163834982; or

[0162] (ii) the gene region, including 2 kb upstream of:

[0163] (2) IKZF 1; and

[0164] (4) GRASP;

[0165] and optionally one or more of (1) BCAT1, (3) IRF4 and (5) CAHM in a biological sample from said individual wherein a higher level of methylation of at least one of the DNA regions of group (i) and/or (ii) relative to control levels is indicative of a large intestine neoplasm or a predisposition to the onset of a large intestine neoplastic state.

[0166] In still yet another embodiment there is provided a method of screening for the onset or predisposition to the onset of or monitoring a large intestine neoplasm in an individual, said method comprising assessing the methylation status of:

[0167] (i) the DNA regions, including 2 kb upstream of the transcription start site, defined by Hg19 coordinates:

[0168] (3) chr6:391739..411443; and

[0169] (4) chr12:52400748..52409671;

[0170] and optionally one or more of (1) chr12:24962958..25102393, (2) chr7:50344378...50472798 and (5) chr6:163834097..163834982; or

[0171] (ii) the gene region, including 2 kb upstream of:

[0172] (3) IRF4; and

[0173] (4) GRASP;

[0174] and optionally one or more of (1) BCAT1, (2) IKZF1 and (5) CAHM in a biological sample from said individual wherein a higher level of methylation of at least one of the DNA regions of group (i) and/or (ii) relative to control levels is indicative of a large intestine neoplasm or a predisposition to the onset of a large intestine neoplastic state.

[0175] In another embodiment there is provided a method of screening for the onset or predisposition to the onset of or monitoring a large intestine neoplasm in an individual, said method comprising assessing the methylation status of:

[0176] (i) the DNA regions, including 2 kb upstream of the transcription start site, defined by Hg19 coordinates:

[0177] (3) chr6:391739..411443; and

[0178] (5) chr6:163834097..163834982;

[0179] and optionally one or more of (1) chr12:24962958..25102393, (2) chr7:50344378...50472798 and (4) chr12:52400748..52409671; or

[0180] (ii) the gene region, including 2 kb upstream of:

[0181] (3) IRF4; and

[0182] (5) CAHM;

[0183] and optionally one or more of (1) BCAT1, (2) IKZF1 and (4) GRASP in a biological sample from said individual wherein a higher level of methylation of at least one of the DNA regions of group (i) and/or (ii) relative to control levels is indicative of a large intestine neoplasm or a predisposition to the onset of a large intestine neoplastic state.

[0184] The subregions which have been determined to exhibit particular utility are listed below with reference to the gene and chromosomal region within which they are found:

[0185] (1) BCAT subregions chr12:25101992-25102093 (SEQ ID NO:1 or corresponding minus strand) and chr12:25101909-25101995 (SEQ ID NO:2 or corresponding minus strand)

[0186] (2) IKZF1 subregions: chr7:50343867-50343961 (SEQ ID NO:3 or corresponding minus strand) and chr7:50343804-5033895 (SEQ ID NO:4 or corresponding minus strand)

[0187] (3) IRF4 subregions chr6:392036-392145 (SEQ ID NO:5 or corresponding minus strand)

[0188] (4) GRASP subregions: chr12:52399672-52399922, chr12:52400821-52401051 (SEQ ID NO:6 or corresponding minus strand), chr12:52401407-52401664 (SEQ ID NO:7 or corresponding minus strand) chr12:52400866-52400973 and Chr12:52401107-52401664.

[0189] (5) CAHM subregions: chr6:163834295-163834500 (SEQ ID NO:8 or corresponding minus strand), chr6:163834621-163834906, chr6:163834393-163834455 and chr6:163834393-163834519.

[0190] To the extent that the method of the present invention includes analyzing the methylation of GRASP, the subject residues are:

TABLE-US-00001 chr12:52399713 chr12:52399731 chr12:52399749 chr12:52399783 chr12:52399796 chr12:52399808 chr12:52399823 chr12:52399835 chr12:52399891 chr12:52400847 chr12:52400850 chr12:52400859 chr12:52400866 chr12:52400869 chr12:52400873 chr12:52400881 chr12:52400886 chr12:52400893 chr12:52400895 chr12:52400899 chr12:52400902 chr12:52400907 chr12:52400913 chr12:52400919 chr12:52400932 chr12:52400938 chr12:52400958 chr12:52400962 chr12:52400971 chr12:52400973 chr12:52400976 chr12:52400998 chr12:52401008 chr12:52401010 chr12:52401012 chr12:52401016 chr12:52401019 chr12:52401025 chr12:52401041 chr12:52401044 chr12:52401053 chr12:52401060 chr12:52401064 chr12:52401092 chr12:52401118 chr12:52401438 chr12:52401448 chr12:52401460 chr12:52401465 chr12:52401474 chr12:52401477 chr12:52401479 chr12:52401483 chr12:52401504 chr12:52401514 chr12:52401523 chr12:52401540 chr12:52401553 chr12:52401576 chr12:52401588 chr12:52401595 chr12:52401599 chr12:52401604 chr12:52401606 chr12:52401634 chr12:52401640 chr12:52401644 chr12:52401659 chr12:52401160 chr12:52401165 chr12:52401174 chr12:52401177 chr12:52401179 chr12:52401183 chr12:52401204 chr12:52401215 chr12:52401223 chr12:52401240 chr12:52401253 chr12:52401288 chr12:52401295 chr12:52401299 chr12:52401304 chr12:52401334 chr12:52401340 chr12:52401344 chr12:52401359

or a corresponding cytosine at position n+1 on the opposite DNA strand.

[0191] To the extent that the method of the present invention includes analyzing CAHM, the subject residues are:

TABLE-US-00002 chr6: 163834330 chr6: 163834332 chr6: 163834357 chr6: 163834373 chr6: 163834384 chr6: 163834390 chr6: 163834392 chr6: 163834406 chr6: 163834412 chr6: 163834419 chr6: 163834443 chr6: 163834448 chr6: 163834452 chr6: 163834464 chr6: 163834483 chr6: 163834653 chr6: 163834660 chr6: 163834672 chr6: 163834675 chr6: 163834678 chr6: 163834681 chr6: 163834815 chr6: 163834824 chr6: 163834835 chr6:163834840 chr6:163834853 chr6:163834855 chr6:163834858 chr6:163834863 chr6:163834869 chr6:163834872

or a corresponding cytosine at position n+1 on the opposite DNA strand.

[0192] To the extent that the method of the present invention includes analyzing IKZF1, the subject residues are:

TABLE-US-00003 chr7: 50343869 chr7:50343872 chr7:50343883 chr7:50343889 chr7:50343890 chr7: 50343897 chr7: 50343907 chr7:50343909 chr7:50343914 chr7:50343934 chr7:50343939 chr7:50343950 chr7:50343959 chr7:50343805 chr7: 50343822 chr7: 50343824 chr7:50343826 chr7: 50343829 chr7:50343831 chr7:50343833 chr7:50343838 chr7: 50343847 chr7:50343850 chr7:50343858 chr7: 50343864 chr7:50343869 chr7: 50343872 chr7: 50343890

or a corresponding cytosine at position n+1 on the opposite DNA strand.

[0193] To the extent that the method of the present invention includes analyzing IRF4, the subject residues are:

TABLE-US-00004 chr6:392036 chr6:392047 chr6:392049 chr6:392057 chr6:392060 chr6:392066 chr6:392080 chr6:392094 chr6:392102 chr6:392131

or a corresponding cytosine at position n+1 on the opposite DNA strand.

[0194] Another aspect of the present invention is directed to a method of screening for the onset or predisposition to the onset of or monitoring a large intestine neoplasm in an individual, said method comprising assessing the level of expression of a DNA region selected from:

[0195] (i) the region, including 2 kb upstream of the transcription start site, defined by any two or more of Hg19 coordinates:

[0196] (1) chr12:24962958..25102393

[0197] (2) chr7:50344378...50472798

[0198] (3) chr6:391739..411443; or

[0199] (4) chr12:52400748..52409671; and

[0200] (5) chr6:163834097..163834982; or

[0201] (ii) the gene region, including 2 kb upstream of any two or more of:

[0202] (1) BCAT1 (2) IKZF1 (3) IRF4 (4) GRASP and (5) CAHM in a biological sample from said individual wherein a lower level of expression of at least one of the DNA regions of group (i) and/or (ii) relative to control levels is indicative of a large intestine neoplasm or a predisposition to the onset of a neoplastic state.

BRIEF DESCRIPTION OF THE DRAWINGS

[0203] FIG. 1 depicts the genomic sequence of GRASP.

[0204] FIG. 2 depicts the genomic sequence of CAHM.

[0205] FIG. 3 depicts the genomic sequence of IRF4.

[0206] FIG. 4 depicts the genomic sequence of BCAT1.

[0207] FIG. 5 depicts the genomic sequence of IKZF 1.

DETAILED DESCRIPTION

[0208] The present invention is predicated, in part, on the determination that the change in methylation pattern of a panel of gene markers can provide a higher level of either diagnostic specificity or diagnostic sensitivity when tested collectively than if any one of these markers is tested either in isolation or together with markers other than those specified herein. This finding has therefore now facilitated the development of an improved test for diagnosing, prognosing or monitoring neoplasms of the large intestine based on assessing the methylation of two or more of the gene markers BCAT1, IKZF1, CAHM, GRASP and IRF4.

[0209] In accordance with the present invention, it has been determined that certain specific panels of genes are modulated, in terms of differential changes to their levels of methylation, depending on whether or not the cell in issue is neoplastic or not. It should be understood that the genes in issue are described herein both by reference to their name and their chromosomal coordinates. The chromosomal coordinates are consistent with the human genome database version Hg19 which was released in February 2009 (herein referred to as "Hg19 coordinates").

[0210] Accordingly, one aspect of the present invention is directed to a method of screening for the onset or predisposition to the onset of or monitoring a large intestine neoplasm in an individual, said method comprising assessing the methylation status of a DNA region selected from:

[0211] (i) the region, including 2 kb upstream of the transcription start site, defined by any two or more of Hg19 coordinates:

[0212] (1) chr12:24962958..25102393

[0213] (2) chr7:50344378...50472798

[0214] (3) chr6:391739..411443;

[0215] (4) chr12:52400748..52409671; and

[0216] (5) chr6:163834097..163834982; or

[0217] (ii) the gene region, including 2 kb upstream of any two or more of:

[0218] (1) BCAT1 (2) IKZF1 (3) IRF4 (4) GRASP and (5) CAHM in a biological sample from said individual wherein a higher level of methylation of at least one of the DNA regions of group (i) and/or (ii) relative to control levels is indicative of a large intestine neoplasm or a predisposition to the onset of a large intestine neoplastic state.

[0219] In one embodiment, said method is directed to identifying biological samples in which any one of said DNA regions exhibits a higher level of methylation.

[0220] In another embodiment, said method is directed to identifying biological samples in which two or more of said DNA regions exhibit a higher level of methylation.

[0221] Without limiting the present invention to any one theory or mode of action, the panel of DNA regions (markers) specified herein provide not only an improved diagnostic outcome relative to prior art methods but, in addition, enable the development of a screening method which can be designed to focus on providing either a high level of diagnostic specificity or a high level of diagnostic sensitivity. As would be understood by the person of skill in the art, in the context of diagnostics "sensitivity" defines the proportion of positive results which are correctly identified, that is, the percentage of individuals correctly identified as having the disease in issue. "Specificity", however, defines the proportion of negative results which are correctly identified, that is, the percentage of individuals correctly identified as not having the disease in issue.

[0222] In the context of the present invention it has been determined that screening a patient sample for the methylation status of the specified panel of markers can be designed to provide either a diagnostic result which exhibits a high level of specificity or a diagnostic result which exhibits a high level of sensitivity.

[0223] Where a high level of sensitivity is sought, the screening method is designed to identify samples in which any one of the markers of the panel exhibits increased methylation relative to control levels. That is, not all of the markers are required to exhibit hypermethylation in order to define the result as positive. Where a higher level of sensitivity is sought, the level of specificity is inherently reduced. However, if it is desired to pursue a higher level of specificity (which may reduce the level of sensitivity) then the method is designed to identify samples in which two or more of the panel of DNA regions exhibit increased methylation.

[0224] Accordingly, to the extent that the present invention is directed to embodiments of the method in which "any one of" the DNA regions (markers) of the specified panel exhibits a higher level of methylation, these embodiments are designed to achieve results exhibiting increased sensitivity based on any one of the markers in the panel being hypermethylated. It should be understood that it need not be the same marker which is hypermethylated in each sample. Rather, it is simply that one of the markers which forms part of the panel is hypermethylated. It should also be understood that in relation to some samples, two or more of the markers of the panel may be hypermethylated. These samples should be understood to nevertheless fall within the scope of this embodiment of the invention since this embodiment is not excluding the situation where multiple markers are hypermethylated but is merely including within its scope all those samples where as few as one marker are hypermethylated. Overall these data will provide increased sensitivity but reduced specificity.

[0225] To the extent that the present invention is directed to embodiments of the method in which "two or more" of the DNA regions (markers) of the specified panel exhibit a higher level of methylation, these embodiments are designed to achieve a higher level of specificity. This is achieved by virtue of the fact that at least two, if not more, of the specified panel of markers are determined to be hypermethylated.

[0226] Reference to "large intestine" should be understood as a reference to a cell derived from one of the eight anatomical regions of the large intestine, which regions commence after the terminal region of the ileum, these being:

[0227] (i) the cecum;

[0228] (ii) the ascending colon;

[0229] (iii) the transverse colon;

[0230] (iv) the descending colon;

[0231] (v) the sigmoid colon;

[0232] (vi) the rectum;

[0233] (vii) the splenic flexure; and

[0234] (viii) the hepatic flexure.

[0235] Reference to "neoplasm" should be understood as a reference to a lesion, tumor or other encapsulated or unencapsulated mass or other form of growth which comprises neoplastic cells. A "neoplastic cell" should be understood as a reference to a cell exhibiting abnormal growth. The term "growth" should be understood in its broadest sense and includes reference to proliferation. In this regard, an example of abnormal cell growth is the uncontrolled proliferation of a cell. Another example is failed apoptosis in a cell, thus prolonging its usual life span. The neoplastic cell may be a benign cell or a malignant cell. In a preferred embodiment, the subject neoplasm is an adenoma or an adenocarcinoma. Without limiting the present invention to any one theory or mode of action, an adenoma is generally a benign tumor of epithelial origin which is either derived from epithelial tissue or exhibits clearly defined epithelial structures. These structures may take on a glandular appearance. It can comprise a malignant cell population within the adenoma, such as occurs with the progression of a benign adenoma or benign neoplastic legion to a malignant adenocarcinoma.

[0236] Preferably, said neoplastic cell is an adenoma or adenocarcinoma and even more preferably a colorectal adenoma or adenocarcinoma.

[0237] Reference to "DNA region" should be understood as a reference to a specific section of genomic DNA. These DNA regions are specified either by reference to a gene name or a set of chromosomal coordinates. Both the gene names and the chromosomal coordinates would be well known to, and understood by, the person of skill in the art. As detailed hereinbefore, the chromosomal coordinates correspond to the Hg19 version of the genome. In general, a gene can be routinely identified by reference to its name, via which both its sequences and chromosomal location can be routinely obtained, or by reference to its chromosomal coordinates, via which both the gene name and its sequence can also be routinely obtained.

[0238] Reference to each of the genes/DNA regions detailed above should be understood as a reference to all forms of these molecules and to fragments or variants thereof. As would be appreciated by the person of skill in the art, some genes are known to exhibit allelic variation between individuals or single nucleotide polymorphisms. SNPs encompass insertions and deletions of varying size and simple sequence repeats, such as dinucleotide and trinucleotide repeats. Variants include nucleic acid sequences from the same region sharing at least 90%, 95%, 98%, 99% sequence identity i.e. having one or more deletions, additions, substitutions, inverted sequences etc. relative to the DNA regions described herein. Accordingly, the present invention should be understood to extend to such variants which, in terms of the present diagnostic applications, achieve the same outcome despite the fact that minor genetic variations between the actual nucleic acid sequences may exist between individuals. The present invention should therefore be understood to extend to all forms of DNA which arise from any other mutation, polymorphic or allelic variation.

[0239] It should be understood that the "individual" who is the subject of testing may be any human or non-human mammal. Examples of non-human mammals includes primates, livestock animals (e.g. horses, cattle, sheep, pigs, donkeys), laboratory test animals (e.g. mice, rats, rabbits, guinea pigs), companion animals (e.g. dogs, cats) and captive wild animals (e.g. deer, foxes).

[0240] Preferably the mammal is a human.

[0241] The panel of genes which has been identified demonstrates increased methylation in large intestine neoplastic cells relative to corresponding non-neoplastic cells. This increased methylation is, in some cases, localized to a few specific CpG sites within the DNA region while in other cases it is observed across a wide range of CpG sites. However, although specific regions from all genes exhibit increased methylation and are therefore useful diagnostic markers, it is the analysis of these specific markers as a panel which has provided an independent and very significant improvement over the sensitivity and specificity could be obtainable over these markers are analyzed individually. This improvement is also significant even when considered against the sensitivity and specificity obtainable using other markers known to exhibit increased methylation as a marker of the onset of a large intestine neoplasm. Accordingly, the method of the present invention has now provided a means of achieving a higher level of sensitivity and specificity than has been achievable to date.

[0242] In one aspect there is provided a method of screening for the onset or predisposition to the onset of or monitoring a large intestine neoplasm in an individual, said method comprising assessing the methylation status of:

[0243] (i) the DNA regions, including 2 kb upstream of the transcription start site, defined by Hg19 coordinates:

[0244] (1) chr12:24962958..25102393; and

[0245] (2) chr7:50344378...50472798;

[0246] and optionally one or more of (3) chr6:391739..411443, (4) chr12:52400748..52409671 and (5) chr6:163834097..163834982; or

[0247] (ii) the gene region, including 2 kb upstream of:

[0248] (1) BCAT1; and

[0249] (2) IKZF1;

[0250] and optionally one or more of (3) IRF4, (4) GRASP and (5) CAHM in a biological sample from said individual wherein a higher level of methylation of at least one of the DNA regions of group (i) and/or (ii) relative to control levels is indicative of a large intestine neoplasm or a predisposition to the onset of a large intestine neoplastic state.

[0251] In one embodiment of this aspect, the gene marker panel which is screened for is:

[0252] (i) the DNA regions, including 2 kb upstream of the transcription start site, defined by Hg19 coordinates:

[0253] (1) chr12:24962958..25102393

[0254] (2) chr7:50344378...50472798; and

[0255] (3) chr6:391739..411443; or

[0256] (ii) the gene region, including 2 kb upstream of:

[0257] (1) BCAT1, (2) IKZF1 and (3) IRF4.

[0258] In another embodiment of this aspect, the gene marker panel which is screened for is:

[0259] (i) the DNA regions, including 2 kb upstream of the transcription start site, defined by Hg19 coordinates:

[0260] (1) chr12:24962958..25102393

[0261] (2) chr7:50344378...50472798 and

[0262] (4) chr12:52400748..52409671; or

[0263] (ii) the gene region, including 2 kb upstream of:

[0264] (1) BCAT1, (2) IKZF1; and (4) GRASP.

[0265] In still another embodiment of this aspect, the gene marker panel which is screened for is:

[0266] (i) the DNA regions, including 2 kb upstream of the transcription start site, defined by Hg19 coordinates:

[0267] (1) chr12:24962958..25102393

[0268] (2) chr7:50344378...50472798 and

[0269] (5) chr6:163834097..163834982; or

[0270] (ii) the gene region, including 2 kb upstream of:

[0271] (1) BCAT1, (2) IKZF1 and (5) CAHM

[0272] In still yet another embodiment of this aspect, the gene marker panel which is screened for is:

[0273] (i) the DNA regions, including 2 kb upstream of the transcription start site, defined by Hg19 coordinates:

[0274] (1) chr12:24962958..25102393

[0275] (2) chr7:50344378...50472798

[0276] (3) chr6:391739..411443; and

[0277] (4) chr12:52400748..52409671; or

[0278] (ii) the gene region, including 2 kb upstream of:

[0279] (1) BCAT1, (2) IKZF1, (3) IRF4 and (4) GRASP.

[0280] In yet still another embodiment of this aspect, the gene marker panel which is screened for is:

[0281] (i) the DNA regions, including 2 kb upstream of the transcription start site, defined by Hg19 coordinates:

[0282] (1) chr12:24962958..25102393

[0283] (2) chr7:50344378...50472798

[0284] (3) chr6:391739..411443; and

[0285] (5) chr6:163834097..163834982; or

[0286] (ii) the gene region, including 2 kb upstream of:

[0287] (1) BCAT1, (2) IKZF1, (3) IRF4 and (5) CAHM

[0288] In a further embodiment of this aspect, the gene marker panel which is screened for is:

[0289] (i) the DNA regions, including 2 kb upstream of the transcription start site, defined by Hg19 coordinates:

[0290] (1) chr12:24962958..25102393

[0291] (2) chr7:50344378...50472798

[0292] (4) chr12:52400748..52409671 and

[0293] (5) chr6:163834097..163834982; or

[0294] (ii) the gene region, including 2 kb upstream of:

[0295] (1) BCAT1, (2) IKZF1, (4) GRASP and (5) CAHM

[0296] In yet another further embodiment of this aspect, the gene marker panel which is screened for is:

[0297] (i) the DNA regions, including 2 kb upstream of the transcription start site, defined by Hg19 coordinates:

[0298] (1) chr12:24962958..25102393

[0299] (2) chr7:50344378...50472798

[0300] (3) chr6:391739..411443

[0301] (4) chr12:52400748..52409671 and

[0302] (5) chr6:163834097..163834982; or

[0303] (ii) the gene region, including 2 kb upstream of:

[0304] (1) BCAT1, (2) IKZF1, (3) IRF4, (4) GRASP and (5) CAHM

[0305] In another embodiment there is provided a method of screening for the onset or predisposition to the onset of or monitoring a large intestine neoplasm in an individual, said method comprising assessing the methylation status of:

[0306] (i) the DNA regions, including 2 kb upstream of the transcription start site, defined by Hg19 coordinates:

[0307] (1) chr12:24962958..25102393; and

[0308] (5) chr6:163834097..163834982;

[0309] and optionally one or more of (2) chr7:50344378...50472798, (3) chr6:391739..411443; and (4) chr12:52400748..52409671; or

[0310] (ii) the gene region, including 2 kb upstream of:

[0311] (1) BCAT1; and

[0312] (5) CAHM;

[0313] and optionally one or more of (2) IKZF 1, (3) IRF4 and (4) GRASP in a biological sample from said individual wherein a higher level of methylation of at least one of the DNA regions of group (i) and/or (ii) relative to control levels is indicative of a large intestine neoplasm or a predisposition to the onset of a large intestine neoplastic state.

[0314] In still another embodiment there is provided a method of screening for the onset or predisposition to the onset of or monitoring a large intestine neoplasm in an individual, said method comprising assessing the methylation status of:

[0315] (i) the DNA regions, including 2 kb upstream of the transcription start site, defined by Hg19 coordinates:

[0316] (2) chr7:50344378..50472798; and

[0317] (5) chr6:163834097..163834982;

[0318] and optionally one or more of (1) chr12:24962958..25102393, (3) chr6:391739..411443 and (4) chr12:52400748..52409671; or

[0319] (ii) the gene region, including 2 kb upstream of:

[0320] (2) IKZF 1; and

[0321] (5) CAHM;

[0322] and optionally one or more of (1) BCAT1, (3) IRF4 and (4) GRASP in a biological sample from said individual wherein a higher level of methylation of at least one of the DNA regions of group (i) and/or (ii) relative to control levels is indicative of a large intestine neoplasm or a predisposition to the onset of a large intestine neoplastic state.

[0323] In a further embodiment there is provided a method of screening for the onset or predisposition to the onset of or monitoring a large intestine neoplasm in an individual, said method comprising assessing the methylation status of:

[0324] (i) the DNA regions, including 2 kb upstream of the transcription start site, defined by Hg19 coordinates:

[0325] (1) chr12:24962958..25102393; and

[0326] (3) chr6:391739..411443;

[0327] and optionally one or more of (2) chr7:50344378...50472798, (4) chr12:52400748..52409671 and (5) chr6:163834097..163834982; or

[0328] (ii) the gene region, including 2 kb upstream of:

[0329] (1) BCAT1; and

[0330] (3) IRF4;

[0331] and optionally one or more of (2) IKZF 1, (4) GRASP and (5) CAHM in a biological sample from said individual wherein a higher level of methylation of at least one of the DNA regions of group (i) and/or (ii) relative to control levels is indicative of a large intestine neoplasm or a predisposition to the onset of a large intestine neoplastic state.

[0332] In yet another further embodiment there is provided a method of screening for the onset or predisposition to the onset of or monitoring a large intestine neoplasm in an individual, said method comprising assessing the methylation status of:

[0333] (i) the DNA regions, including 2 kb upstream of the transcription start site, defined by Hg19 coordinates:

[0334] (1) chr12:24962958..25102393; and

[0335] (4) chr12:52400748..52409671;

[0336] and optionally one or more of (2) chr7:50344378...50472798, (3) chr6:391739..411443 and (5) chr6:163834097..163834982; or

[0337] (ii) the gene region, including 2 kb upstream of:

[0338] (1) BCAT1; and

[0339] (4) GRASP;

[0340] and optionally one or more of (2) IKZF1, (3) IRF4 and (5) CAHM in a biological sample from said individual wherein a higher level of methylation of at least one of the DNA regions of group (i) and/or (ii) relative to control levels is indicative of a large intestine neoplasm or a predisposition to the onset of a large intestine neoplastic state.

[0341] In still another further embodiment there is provided a method of screening for the onset or predisposition to the onset of or monitoring a large intestine neoplasm in an individual, said method comprising assessing the methylation status of:

[0342] (i) the DNA regions, including 2 kb upstream of the transcription start site, defined by Hg19 coordinates:

[0343] (2) chr7:50344378..50472798; and

[0344] (3) chr6:391739..411443;

[0345] and optionally one or more of (1) chr12:24962958..25102393, (4) chr12:52400748..52409671 and (5) chr6:163834097..163834982; or

[0346] (ii) the gene region, including 2 kb upstream of:

[0347] (2) IKZF 1; and

[0348] (3) IRF4;

[0349] and optionally one or more of (1) BCAT1, (4) GRASP and (5) CAHM in a biological sample from said individual wherein a higher level of methylation of at least one of the DNA regions of group (i) and/or (ii) relative to control levels is indicative of a large intestine neoplasm or a predisposition to the onset of a large intestine neoplastic state.

[0350] In yet still another embodiment there is provided a method of screening for the onset or predisposition to the onset of or monitoring a large intestine neoplasm in an individual, said method comprising assessing the methylation status of:

[0351] (i) the DNA regions, including 2 kb upstream of the transcription start site, defined by Hg19 coordinates:

[0352] (2) chr7:50344378..50472798; and

[0353] (4) chr12:52400748..52409671;

[0354] and optionally one or more of (1) chr12:24962958..25102393, (3) chr6:391739..411443 and (5) chr6:163834097..163834982; or

[0355] (ii) the gene region, including 2 kb upstream of:

[0356] (2) IKZF 1; and

[0357] (4) GRASP;

[0358] and optionally one or more of (1) BCAT1, (3) IRF4 and (5) CAHM in a biological sample from said individual wherein a higher level of methylation of at least one of the DNA regions of group (i) and/or (ii) relative to control levels is indicative of a large intestine neoplasm or a predisposition to the onset of a large intestine neoplastic state.

[0359] In still yet another embodiment there is provided a method of screening for the onset or predisposition to the onset of or monitoring a large intestine neoplasm in an individual, said method comprising assessing the methylation status of:

[0360] (i) the DNA regions, including 2 kb upstream of the transcription start site, defined by Hg19 coordinates:

[0361] (3) chr6:391739..411443; and

[0362] (4) chr12:52400748..52409671;

[0363] and optionally one or more of (1) chr12:24962958..25102393, (2) chr7:50344378...50472798 and (5) chr6:163834097..163834982; or

[0364] (ii) the gene region, including 2 kb upstream of:

[0365] (3) IRF4; and

[0366] (4) GRASP;

[0367] and optionally one or more of (1) BCAT1, (2) IKZF1 and (5) CAHM in a biological sample from said individual wherein a higher level of methylation of at least one of the DNA regions of group (i) and/or (ii) relative to control levels is indicative of a large intestine neoplasm or a predisposition to the onset of a large intestine neoplastic state.

[0368] In another embodiment there is provided a method of screening for the onset or predisposition to the onset of or monitoring a large intestine neoplasm in an individual, said method comprising assessing the methylation status of:

[0369] (i) the DNA regions, including 2 kb upstream of the transcription start site, defined by Hg19 coordinates:

[0370] (3) chr6:391739..411443; and

[0371] (5) chr6:163834097..163834982;

[0372] and optionally one or more of (1) chr12:24962958..25102393, (2) chr7:50344378...50472798 and (4) chr12:52400748..52409671; or

[0373] (ii) the gene region, including 2 kb upstream of:

[0374] (3) IRF4; and

[0375] (5) CAHM;

[0376] and optionally one or more of (1) BCAT1, (2) IKZF1 and (4) GRASP in a biological sample from said individual wherein a higher level of methylation of at least one of the DNA regions of group (i) and/or (ii) relative to control levels is indicative of a large intestine neoplasm or a predisposition to the onset of a large intestine neoplastic state.

[0377] In accordance with these aspects and embodiments, in yet another embodiment said control level is a non-neoplastic level.

[0378] In one embodiment, said method is directed to identifying biological samples in which any one of said DNA regions exhibits a higher level of methylation.

[0379] In another embodiment, said method is directed to identifying biological samples in which two or more of said DNA regions exhibits a higher level of methylation.

[0380] Still further, in another embodiment, said large intestine tissue is preferably colorectal tissue.

[0381] In still another embodiment, the neoplasm is malignant, such as a carcinoma.

[0382] In a further embodiment, the neoplasm is non-malignant, such as an adenoma.

[0383] In terms of screening for the methylation of these gene regions, it should be understood that the assays can be designed to screen either the specific regions listed herein (which correspond to the "plus" strand of the gene) or the complementary "minus" strand. It is well within the skill of the person in the art to choose which strand to analyze and to target that strand based on the chromosomal coordinates provided herein. In some circumstances, assays may be established to screen both strands.

[0384] It should be understood that one may screen for the specified panel of markers exclusively or one may elect to additionally screen for other markers, such as other DNA hypermethylation markers, other RNA expression level markers or other protein markers. These other markers may, for example, provide additional information in relation to the health status of the patient in issue.

[0385] Without limiting the present invention to any one theory or mode of action, although measuring the methylation levels across these DNA regions is diagnostic of a large intestine neoplastic condition, it has been determined that discrete subregions are particularly useful in this regard since these subregions contain a high density of CpG dinucleotides which are frequently hypermethylated in large intestine neoplasias, such as colorectal cancers. This finding renders these subregions a particularly useful target for analysis since it both simplifies the screening process due to a shorter more clearly defined region of DNA requiring analysis and, further, the fact that the results from these regions will provide a significantly more definitive result in relation to the presence, or not, of hypermethylation than would be obtained if analysis was performed across the DNA region as a whole. This finding therefore both simplifies the screening process and increases the sensitivity and specificity of large intestine neoplasia diagnosis.

[0386] The subregions which have been determined to exhibit particular utility are listed below with reference to the gene and chromosomal region within which they are found:

[0387] (1) BCAT subregions chr12:25101992-25102093 (SEQ ID NO:1 or corresponding minus strand) and chr12:25101909-25101995 (SEQ ID NO:2 or corresponding minus strand)

[0388] (2) IKZF1 subregions: chr7:50343867-50343961 (SEQ ID NO:3 or corresponding minus strand) and chr7:50343804-5033895 (SEQ ID NO:4 or corresponding minus strand)

[0389] (3) IRF4 subregions chr6:392036-392145 (SEQ ID NO:5 or corresponding minus strand)

[0390] (4) GRASP subregions: chr12:52399672-52399922, chr12:52400821-52401051 (SEQ ID NO:6 or corresponding minus strand), chr12:52401407-52401664 (SEQ ID NO:7 or corresponding minus strand) chr12:52400866-52400973 and Chr12:52401107-52401664.

[0391] (5) CAHM subregions: chr6:163834295-163834500 (SEQ ID NO:8), chr6:163834621-163834906, chr6:163834393-163834455 and chr6:163834393-163834519.

[0392] Without limiting the present invention to any one theory or mode of action, the skilled person may screen one or more subregions for each gene marker.

[0393] In one embodiment, the methylation marker subregions tested for each selected gene marker are:

[0394] (1) The BCAT subregion defined by SEQ ID NO:1 or SEQ ID NO:2 or corresponding minus strand;

[0395] (2) The IKZF1 subregion defined by SEQ ID NO:3 or SEQ ID NO:4 or corresponding minus strand;

[0396] (3) The IRF4 subregion defined by SEQ ID NO:5 or corresponding minus strand;

[0397] (4) The GRASP subregion defined by SEQ ID NO:6 or 7 or corresponding minus strands; and

[0398] (5) The CAHM subregion defined by SEQ ID NO:8 or corresponding minus strand.

[0399] Without limiting the present invention to any one theory or mode of action, DNA methylation is universal in bacteria, plants, and animals. DNA methylation is a type of chemical modification of DNA that is stable over rounds of cell division but does not involve changes in the underlying DNA sequence of the organism. Chromatin and DNA modifications are two important features of epigenetics and play a role in the process of cellular differentiation, allowing cells to stably maintain different characteristics despite containing the same genomic material. In eukaryotic organisms DNA methylation occurs only at the number 5 carbon of the cytosine pyrimidine ring. In mammals, DNA methylation occurs mostly at the number 5 carbon of the cytosine of a CpG dinucleotide. CpG dinucleotides comprise approximately 1% human genome.

[0400] 70-80% of all CpGs are methylated. CpGs may be grouped in clusters called "CpG islands" that are present in the 5' regulatory regions of many genes and are frequently unmethylated. In many disease processes such as cancer, gene promoters and/or CpG islands acquire abnormal hypermethylation, which is associated with heritable transcriptional silencing. DNA methylation may impact the transcription of genes in two ways. First, the methylation of DNA may itself physically impede the binding of transcriptional proteins to the gene, thus blocking transcription. Second, methylated DNA may be bound by proteins known as Methyl-CpG-binding domain proteins (MBDs). MBD proteins then recruit additional proteins to the locus, such as histone deacetylases and other chromatin remodeling proteins that can modify histones, thereby forming compact, inactive chromatin termed silent chromatin. This link between DNA methylation and chromatin structure is very important. In particular, loss of Methyl-CpG-binding Protein 2 (MeCP2) has been implicated in Rett syndrome and Methyl-CpG binding domain protein 2 (MBD2) mediates the transcriptional silencing of hypermethylated genes in cancer.

[0401] In humans, the process of DNA methylation is carried out by three enzymes, DNA methyltransferase 1, 3a and 3b (DNMT1, DNMT3a, DNMT3b). It is thought that DNMT3a and DNMT3b are the de novo methyltransferases that set up DNA methylation patterns early in development. DNMT1 is the proposed maintenance methyltransferase that is responsible for copying DNA methylation patterns to the daughter strands during DNA replication. DNMT3L is a protein that is homologous to the other DNMT3s but has no catalytic activity. Instead, DNMT3L assists the de novo methyltransferases by increasing their ability to bind to DNA and stimulating their activity. Finally, DNMT2 has been identified as an "enigmatic" DNA methyltransferase homolog, containing all 10 sequence motifs common to all DNA methyltransferases; however, DNMT2 may not methylate DNA but instead has been shown to methylate a small RNA.

[0402] "Methylation status" should therefore be understood as a reference to the presence, absence and/or quantity of methylation at a particular nucleotide, or nucleotides, within a DNA region. The methylation status of a particular DNA sequence (e.g. DNA region as described herein) can indicate the methylation state of every base in the sequence or can indicate the methylation state of a subset of the base pairs (e.g., of cytosines or the methylation state of one or more specific restriction enzyme recognition sequences) within the sequence, or can indicate information regarding regional methylation density within the sequence without providing precise information of where in the sequence the methylation occurs. The methylation status can optionally be represented or indicated by a "methylation value." A methylation value can be generated, for example, by quantifying the amount of intact DNA present following restriction digestion with a methylation dependent restriction enzyme. In this example, if a particular sequence in the DNA is quantified using quantitative PCR, an amount of template DNA approximately equal to a mock treated control indicates the sequence is not highly methylated whereas an amount of template substantially less than occurs in the mock treated sample indicates the presence of methylated DNA at the sequence. Accordingly, a value, i.e., a methylation value, for example from the above-described example, represents the methylation status and can thus be used as a quantitative indicator of the methylation status. This is of particular use when it is desirable to compare the methylation status of a sequence in a sample to a threshold value.

[0403] The method of the present invention is predicated on the comparison of the level of methylation of specific DNA regions of a biological sample with the control methylation levels of these DNA regions. The "control level" is the "normal level", which is the level of methylation of the DNA region of a corresponding large intestine cell or cellular population which is not neoplastic or in another biological sample from which DNA may be isolated for assay.

[0404] The normal (or "non-neoplastic") methylation level may be determined using non-neoplastic tissues derived from the same individual who is the subject of testing. However, it would be appreciated that this may be quite invasive for the individual concerned and it is therefore likely to be more convenient to analyze the test results relative to a standard result which reflects individual or collective results obtained from individuals other than the patient in issue. This latter form of analysis is in fact the preferred method of analysis since it enables the design of kits which require the collection and analysis of a single biological sample, being a test sample of interest. The standard results which provide the normal methylation level may be calculated by any suitable means which would be well known to the person of skill in the art. For example, a population of normal tissues can be assessed in terms of the level of methylation of the genes of the present invention, thereby providing a standard value or range of values against which all future test samples are analyzed. It should also be understood that the normal level may be determined from the subjects of a specific cohort and for use with respect to test samples derived from that cohort. Accordingly, there may be determined a number of standard values or ranges which correspond to cohorts which differ in respect of characteristics such as age, gender, ethnicity or health status. Said "normal level" may be a discrete level or a range of levels. An increase in the methylation level of the subject genes relative to normal levels is indicative of the tissue being neoplastic.

[0405] The term "methylation" shall be taken to mean the presence of a methyl group added by the action of a DNA methyl transferase enzyme to a cytosine base or bases in a region of nucleic acid, e.g. genomic DNA. As described herein, there are several methods known to those skilled in the art for determining the level or degree of methylation of nucleic acid.

[0406] By "higher level" is meant that there are a higher number of methylated CpG dinucleotides in the subject diagnosed than in a control sample, that is, either the proportion of DNA molecules methylated at a particular CpG site is higher or there are a higher number of separate CpG sites methylated in the subject. It should be understood that the terms "enhanced" and "increased" are used interchangeably with the term "higher".

[0407] In relation to detecting a "higher level" of methylation, it should be understood that in some situations the normal/control level will in fact correspond to the absence of any detectable methylation while the neoplastic level will correspond to the presence of methylation, per se. In this situation the diagnostic method is relatively simple since one need only screen for the mere presence of methylation (i.e. a qualitative assessment only), rather than assessing the methylation levels relative to a control level of methylation, which analysis necessarily involves a measure of quantification. Without limiting the present invention in any way, it is observed in blood-derived samples, for example, that in the context of some markers the change in methylation of that marker upon the onset of neoplasia is a shift from undetectable levels of methylation to the presence of detectable methylation. In these situations a relatively simple qualitative assessment is enabled where one need only screen a test sample to determine the presence or not of methylation. In the context of the definitions provided herein, reference to "higher level" encompasses both a relative increase in the level of methylation of a marker or the onset of methylation where previously none was evident. As detailed hereinbefore, the control level may be newly assessed for each patient or there may be a standard result against which all test samples are assessed. Where it is known that methylation is not present on the marker of interest, one need only screen for the presence or not of methylation since the control level is the absence of methylation and the "higher level" is thereby the presence of any amount of methylation.

[0408] The present invention is not to be limited by a precise number of methylated residues that are considered to be diagnostic of neoplasia in a subject, because some variation between patient samples will occur. The present invention is also not limited by positioning of the methylated residue.

[0409] Nevertheless, a number of specific cytosine residues which undergo hypermethylation within these subregions have also been identified. In another embodiment, therefore, a screening method can be employed which is specifically directed to assessing the methylation status of one or more of either these residues or the corresponding cytosine at position n+1 on the opposite DNA strand.

[0410] To this end, detailed in Table 1 are the cytosine residues which have been identified in this regard. It should be appreciated by the person of skill in the art that these individual residues are numbered by reference to Hg19, which also corresponds to the numbering of the specific subregions listed hereinbefore and which can be further identified when the coordinate numbering for each subregion is applied to the corresponding subregion sequences which are provided in the sequence listing. It should be understood that these residues have been identified in the context of the subregion DNA. However, there are other residues which are hypermethylated outside the subregions themselves but within the larger DNA region from which the subregions derive. Accordingly, these specified residues represent a particularly useful subset of individual cytosine residues which undergo hypermethylation within the context of the DNA regions and subregions herein disclosed. These individual residues are grouped below according to the DNA region within which they occur. These DNA regions are identified by reference to both the Hg19 chromosomal coordinates and the gene region name.

[0411] To the extent that the method of the present invention includes analyzing the methylation of GRASP, the subject residues are:

TABLE-US-00005 chr12:52399713 chr12:52399731 chr12:52399749 chr12:52399783 chr12:52399796 chr12:52399808 chr12:52399823 chr12:52399835 chr12:52399891 chr12:52400847 chr12:52400850 chr12:52400859 chr12:52400866 chr12:52400869 chr12:52400873 chr12:52400881 chr12:52400886 chr12:52400893 chr12:52400895 chr12:52400899 chr12:52400902 chr12:52400907 chr12:52400913 chr12:52400919 chr12:52400932 chr12:52400938 chr12:52400958 chr12:52400962 chr12:52400971 chr12:52400973 chr12:52400976 chr12:52400998 chr12:52401008 chr12:52401010 chr12:52401012 chr12:52401016 chr12:52401019 chr12:52401025 chr12:52401041 chr12:52401044 chr12:52401053 chr12:52401060 chr12:52401064 chr12:52401092 chr12:52401118 chr12:52401438 chr12:52401448 chr12:52401460 chr12:52401465 chr12:52401474 chr12:52401477 chr12:52401479 chr12:52401483 chr12:52401504 chr12:52401514 chr12:52401523 chr12:52401540 chr12:52401553 chr12:52401576 chr12:52401588 chr12:52401595 chr12:52401599 chr12:52401604 chr12:52401606 chr12:52401634 chr12:52401640 chr12:52401644 chr12:52401659 chr12:52401160 chr12:52401165 chr12:52401174 chr12:52401177 chr12:52401179 chr12:52401183 chr12:52401204 chr12:52401215 chr12:52401223 chr12:52401240 chr12:52401253 chr12:52401288 chr12:52401295 chr12:52401299 chr12:52401304 chr12:52401334 chr12:52401340 chr12:52401344 chr12:52401359

or a corresponding cytosine at position n+1 on the opposite DNA strand.

[0412] To the extent that the method of the present invention includes analyzing CAHM, the subject residues are:

TABLE-US-00006 chr6: 163834330 chr6:163834332 chr6: 163834357 chr6: 163834373 chr6:163834384 chr6: 163834390 chr6: 163834392 chr6:163834406 chr6: 163834412 chr6: 163834419 chr6:163834443 chr6: 163834448 chr6: 163834452 chr6:163834464 chr6: 163834483 chr6: 163834653 chr6:163834660 chr6: 163834672 chr6: 163834675 chr6:163834678 chr6: 163834681 chr6: 163834815 chr6:163834824 chr6: 163834835 chr6: 163834840 chr6:163834853 chr6: 163834855 chr6: 163834858 chr6:163834863 chr6: 163834869 chr6: 163834872

or a corresponding cytosine at position n+1 on the opposite DNA strand.

[0413] To the extent that the method of the present invention includes analyzing IKZF 1, the subject residues are:

TABLE-US-00007 chr7: 50343869 chr7: 50343872 chr7:50343883 chr7:50343889 chr7:50343890 chr7: 50343897 chr7: 50343907 chr7:50343909 chr7:50343914 chr7:50343934 chr7:50343939 chr7:50343950 chr7:50343959 chr7:50343805 chr7: 50343822 chr7: 50343824 chr7:50343826 chr7: 50343829 chr7:50343831 chr7:50343833 chr7:50343838 chr7: 50343847 chr7:50343850 chr7:50343858 chr7: 50343864 chr7:50343869 chr7: 50343872 chr7: 50343890

or a corresponding cytosine at position n+1 on the opposite DNA strand.

[0414] To the extent that the method of the present invention includes analyzing IRF4, the subject residues are:

TABLE-US-00008 chr6:392036 chr6:392047 chr6:392049 chr6:392057 chr6:392060 chr6:392066 chr6:392080 chr6:392094 chr6:392102 chr6:392131

or a corresponding cytosine at position n+1 on the opposite DNA strand.

[0415] The detection method of the present invention can be performed on any suitable biological sample. To this end, reference to a "biological sample" should be understood as a reference to any sample of biological material derived from an animal such as, but not limited to, cellular material, biofluids (e.g. blood), feces, tissue biopsy specimens, surgical specimens or fluid which has been introduced into the body of an animal and subsequently removed (such as, for example, the solution retrieved from an enema wash). The biological sample which is tested according to the method of the present invention may be tested directly or may require some form of treatment prior to testing. For example, a biopsy or surgical sample may require homogenization prior to testing or it may require sectioning for in situ testing of the qualitative expression levels of individual genes. Alternatively, a cell sample may require permeabilization prior to testing. Further, to the extent that the biological sample is not in liquid form, (if such form is required for testing) it may require the addition of a reagent, such as a buffer, to mobilize the sample.

[0416] To the extent that the DNA region of interest is present in a biological sample, the biological sample may be directly tested or else all or some of the nucleic acid present in the biological sample may be isolated prior to testing. In yet another example, the sample may be partially purified or otherwise enriched prior to analysis. For example, to the extent that a biological sample comprises a very diverse cell population, it may be desirable to enrich for a sub-population of particular interest. It is within the scope of the present invention for the target cell population or molecules derived therefrom to be treated prior to testing, for example, inactivation of live virus. It should also be understood that the biological sample may be freshly harvested or it may have been stored (for example by freezing) prior to testing or otherwise treated prior to testing (such as by undergoing culturing).

[0417] The choice of what type of sample is most suitable for testing in accordance with the method disclosed herein will be dependent on the nature of the situation. Preferably, said sample is a fecal (stool) sample, enema wash, surgical resection, tissue biopsy or blood sample (e.g. whole blood, serum or plasma).

[0418] More preferably, said biological sample is a blood sample, biopsy sample or stool sample.

[0419] As detailed hereinbefore, the present invention is designed to screen for a neoplastic cell or cellular population, which is located in the large intestine. Accordingly, reference to "cell or cellular population" should be understood as a reference to an individual cell or a group of cells. Said group of cells may be a diffuse population of cells, a cell suspension, an encapsulated population of cells or a population of cells which take the form of tissue.

[0420] Reference to the "onset" of a neoplasm, such as adenoma or adenocarcinoma, should be understood as a reference to one or more cells of that individual exhibiting dysplasia. In this regard, the adenoma or adenocarcinoma may be well developed in that a mass of dysplastic cells has developed. Alternatively, the adenoma or adenocarcinoma may be at a very early stage in that only relatively few abnormal cell divisions have occurred at the time of diagnosis. The present invention also extends to the assessment of an individual's predisposition to the development of a neoplasm, such as an adenoma or adenocarcinoma. Without limiting the present invention in any way, changed methylation levels may be indicative of that individual's predisposition to developing a neoplasia, such as the future development of an adenoma or adenocarcinoma or another adenoma or adenocarcinoma.

[0421] Although the preferred method is to assess methylation levels for the purpose of diagnosing neoplasia development or predisposition thereto, the detection of converse changes in the levels of said methylation may be desired under certain circumstances, for example, to monitor the effectiveness of therapeutic or prophylactic treatment directed to modulating a neoplastic condition, such as adenoma or adenocarcinoma development. For example, where elevated levels of methylation indicate that an individual has developed a condition characterized by adenoma or adenocarcinoma development, screening for a decrease in the levels of methylation subsequently to the onset of a therapeutic treatment regime may be utilized to indicate successful clearance of the neoplastic cells. In another example, one can use this method to test the tissue at the margins of a tumor resection in order to determine whether the full margin of the tumor has been removed.

[0422] The present method can therefore be used in the diagnosis, prognosis, classification, prediction of disease risk, detection of recurrence of disease, selection of treatment of a number of types of neoplasias and monitoring of neoplasias. A cancer at any stage of progression can be detected, such as primary, metastatic, and recurrent cancers.

[0423] The present invention provides methods for determining whether a mammal (e.g., a human) has a neoplasia of the large intestine, whether a biological sample taken from a mammal contains neoplastic cells or DNA derived from neoplastic cells, estimating the risk or likelihood of a mammal developing a neoplasm, monitoring the efficacy of anti-cancer treatment, or selecting the appropriate anti-cancer treatment in a mammal with cancer. Such methods are based on the determination that neoplastic cells have a different methylation status than normal cells in the DNA regions described herein. Accordingly, by determining whether or not a cell contains differentially methylated sequences in the DNA regions as described herein, it is possible to determine that a cell is neoplastic.

[0424] The method of the invention can be used to evaluate individuals known or suspected to have a neoplasia or as a routine clinical test, i.e., in an individual not necessarily suspected to have a neoplasia. Further diagnostic assays can be performed to confirm the status of neoplasia in the individual.

[0425] Further, the present methods may be used to assess the efficacy of a course of treatment. For example, the efficacy of an anti-cancer treatment can be assessed by monitoring DNA methylation of the sequences described herein over time in a mammal having cancer. For example, a reduction or absence of methylation in any of the diagnostic sequences of the invention in a biological sample taken from a mammal following a treatment, compared to a level in a sample taken from the mammal before, or earlier in, the treatment, indicates efficacious treatment.

[0426] The method of the present invention is therefore useful as a one-time test or as an on-going monitor of those individuals thought to be at risk of neoplasia development or as a monitor of the effectiveness of therapeutic or prophylactic treatment regimens directed to inhibiting or otherwise slowing neoplasia development. In these situations, mapping the modulation of methylation levels in any one or more classes of biological samples is a valuable indicator of the status of an individual or the effectiveness of a therapeutic or prophylactic regime which is currently in use. Accordingly, the method of the present invention should be understood to extend to monitoring for increases or decreases in methylation levels in an individual relative to their normal level (as hereinbefore defined), or relative to one or more earlier methylation levels determined from a biological sample of said individual.

[0427] The methods for detecting neoplasia can comprise the detection of one or more other cancer-associated polynucleotide or polypeptides sequences. Accordingly, detection of methylation by the method of the invention can be used either alone, or in combination with other screening methods for the diagnosis or prognosis of neoplasia.

[0428] Any method for detecting DNA methylation can be used in the methods of the present invention. A number of methods are available for detection of differentially methylated DNA at specific loci in either primary tissue samples or in patient samples such as blood, urine, stool or saliva (reviewed in Kristensen and Hansen Clin Chem. 55:1471-83, 2009; Ammerpohl et al. Biochim Biophys Acta. 1790:847-62, 2009; Shames et al. Cancer Lett. 251:187-98, 2007; Clark et al. Nat Protoc. 1:2353-64, 2006). For analysis of the proportion or extent of DNA methylation in a target gene, DNA is normally treated with sodium bisulfite and regions of interest amplified using primers and PCR conditions that will amplify independently of the methylation status of the DNA. The methylation of the overall amplicon or individual CpG sites can then be assessed by sequencing, including pyrosequencing, restriction enzyme digestion (COBRA) or by melting curve analysis. Alternatively ligation-based methods for analysis of methylation at specific CpG sites may be used. Detection of aberrantly methylated DNA released from tumors and into bodily fluids is being developed as a means of cancer diagnosis. Here, in the case of hypermethylated sequences, it is necessary to use sensitive methods that allow the selective amplification of the methylated DNA sequence from a background of normal cellular DNA that is unmethylated. Such methods based on bisulfite-treated DNA, for example; include methylation selective PCR (MSP), Heavymethyl PCR, Headloop PCR and Helper-dependent chain reaction (PCT/AU2008/001475).

[0429] Briefly, in some embodiments, methods for detecting methylation include randomly shearing or randomly fragmenting the genomic DNA, cutting the DNA with a methylation-dependent or methylation-sensitive restriction enzyme and subsequently selectively identifying and/or analyzing the cut or uncut DNA. Selective identification can include, for example, separating cut and uncut DNA (e.g., by size) and quantifying a sequence of interest that was cut or, alternatively, that was not cut. See, e.g., U.S. Pat. No. 7,186,512. Alternatively, the method can encompass amplifying intact DNA after restriction enzyme digestion, thereby only amplifying DNA that was not cleaved by the restriction enzyme in the area amplified. See, e.g., U.S. patent application Ser. Nos. 10/971,986; 11/071,013; and 10/971,339. In some embodiments, amplification can be performed using primers that are gene specific. Alternatively, adaptors can be added to the ends of the randomly fragmented DNA, the DNA can be digested with a methylation-dependent or methylation-sensitive restriction enzyme, intact DNA can be amplified using primers that hybridize to the adaptor sequences. In this case, a second step can be performed to determine the presence, absence or quantity of a particular gene in an amplified pool of DNA. In some embodiments, the DNA is amplified using real-time, quantitative PCR.

[0430] In some embodiments, the methods comprise quantifying the average methylation density in a target sequence within a population of genomic DNA. In some embodiments, the method comprises contacting genomic DNA with a methylation-dependent restriction enzyme or methylation-sensitive restriction enzyme under conditions that allow for at least some copies of potential restriction enzyme cleavage sites in the locus to remain uncleaved; quantifying intact copies of the locus; and comparing the quantity of amplified product to a control value representing the quantity of methylation of control DNA, thereby quantifying the average methylation density in the locus compared to the methylation density of the control DNA.

[0431] The quantity of methylation of a locus of DNA can be determined by providing a sample of genomic DNA comprising the locus, cleaving the DNA with a restriction enzyme that is either methylation-sensitive or methylation-dependent, and then quantifying the amount of intact DNA or quantifying the amount of cut DNA at the DNA locus of interest. The amount of intact or cut DNA will depend on the initial amount of genomic DNA containing the locus, the amount of methylation in the locus, and the number (i.e., the fraction) of nucleotides in the locus that are methylated in the genomic DNA. The amount of methylation in a DNA locus can be determined by comparing the quantity of intact DNA or cut DNA to a control value representing the quantity of intact DNA or cut DNA in a similarly-treated DNA sample. The control value can represent a known or predicted number of methylated nucleotides. Alternatively, the control value can represent the quantity of intact or cut DNA from the same locus in another (e.g., normal, non-diseased) cell or a second locus.

[0432] By using at least one methylation-sensitive or methylation-dependent restriction enzyme under conditions that allow for at least some copies of potential restriction enzyme cleavage sites in the locus to remain uncleaved and subsequently quantifying the remaining intact copies and comparing the quantity to a control, average methylation density of a locus can be determined. A methylation-sensitive enzyme is one which cuts DNA if its recognition sequence is unmethylated while a methylation-dependent enzyme cuts DNA if its recognition sequence is methylated. If the methylation-sensitive restriction enzyme is contacted to copies of a DNA locus under conditions that allow for at least some copies of potential restriction enzyme cleavage sites in the locus to remain uncleaved, then the remaining intact DNA will be directly proportional to the methylation density, and thus may be compared to a control to determine the relative methylation density of the locus in the sample. Similarly, if a methylation-dependent restriction enzyme is contacted to copies of a DNA locus under conditions that allow for at least some copies of potential restriction enzyme cleavage sites in the locus to remain uncleaved, then the remaining intact DNA will be inversely proportional to the methylation density, and thus may be compared to a control to determine the relative methylation density of the locus in the sample. Such assays are disclosed in, e.g., U.S. patent application Ser. No. 10/971,986.

[0433] Kits for the above methods can include, e.g., one or more of methylation-dependent restriction enzymes, methylation-sensitive restriction enzymes, amplification (e.g., PCR) reagents, probes and/or primers.

[0434] Quantitative amplification methods (e.g., quantitative PCR or quantitative linear amplification) can be used to quantify the amount of intact DNA within a locus flanked by amplification primers following restriction digestion. Methods of quantitative amplification are disclosed in, e.g., U.S. Pat. Nos. 6,180,349; 6,033,854; and 5,972,602, as well as in, e.g., Gibson et al., Genome Research 6:995-1001 (1996); DeGraves, et al., Biotechniques 34(1):106-10, 112-5 (2003); Deiman B, et al., Mol. Biotechnol. 20(2):163-79 (2002). Amplifications may be monitored in "real time."

[0435] Additional methods for detecting DNA methylation can involve genomic sequencing before and after treatment of the DNA with bisulfite. See, e.g., Frommer et al., Proc. Natl. Acad. Sci. USA 89:1827-1831 (1992). When sodium bisulfite is contacted to DNA, unmethylated cytosine is converted to uracil, while methylated cytosine is not modified.

[0436] In some embodiments, restriction enzyme digestion of PCR products amplified from bisulfite-converted DNA is used to detect DNA methylation. See, e.g., Sadri & Hornsby, Nucl. Acids Res. 24:5058-5059 (1996); Xiong & Laird, Nucleic Acids Res. 25:2532-2534 (1997).

[0437] In some embodiments, a methylation-specific PCR ("MSP") reaction is used alone or in combination with other methods to detect DNA methylation. An MSP assay entails initial modification of DNA by sodium bisulfite, converting all unmethylated, but not methylated, cytosines to uracil, and subsequent amplification with primers specific for methylated verses unmethylated DNA. See, Herman et al. Proc. Natl. Acad. Sci. USA 93:9821-9826 (1996); U.S. Pat. No. 5,786,146.

[0438] In some embodiments, a MethyLight assay is used alone or in combination with other methods to detect DNA methylation (see, Eads et al., Cancer Res. 59:2302-2306 (1999)). Briefly, in the MethyLight process genomic DNA is converted in a sodium bisulfite reaction (the bisulfite process converts unmethylated cytosine residues to uracil). Amplification of a DNA sequence of interest is then performed using PCR primers that hybridize to CpG dinucleotides. By using primers that hybridize only to sequences resulting from bisulfite conversion of methylated DNA, (or alternatively to unmethylated sequences) amplification can indicate methylation status of sequences where the primers hybridize. Furthermore, the amplification product can be detected with a probe that specifically binds to a sequence resulting from bisulfite treatment of a unmethylated DNA. If desired, both primers and probes can be used to detect methylation status. Thus, kits for use with MethyLight can include sodium bisulfite as well as primers or detectably-labeled probes (including but not limited to Taqman or molecular beacon probes) that distinguish between methylated and unmethylated DNA that have been treated with bisulfite. Other kit components can include, e.g., reagents necessary for amplification of DNA including but not limited to, PCR buffers, deoxynucleotides; and a thermostable polymerase.

[0439] In some embodiments, a Ms-SNuPE (Methylation-sensitive Single Nucleotide Primer Extension) reaction is used alone or in combination with other methods to detect DNA methylation (see, Gonzalgo & Jones, Nucleic Acids Res. 25:2529-2531 (1997)). The Ms-SNuPE technique is a quantitative method for assessing methylation differences at specific CpG sites based on bisulfite treatment of DNA, followed by single-nucleotide primer extension (Gonzalgo & Jones, supra). Briefly, genomic DNA is reacted with sodium bisulfite to convert unmethylated cytosine to uracil while leaving 5-methylcytosine unchanged. Amplification of the desired target sequence is then performed using PCR primers specific for bisulfite-converted DNA, and the resulting product is isolated and used as a template for methylation analysis at the CpG site(s) of interest.

[0440] Typical reagents (e.g., as might be found in a typical Ms-SNuPE-based kit) for Ms-SNuPE analysis can include, but are not limited to: PCR primers for specific gene (or methylation-altered DNA sequence or CpG island); optimized PCR buffers and deoxynucleotides; gel extraction kit; positive control primers; Ms-SNuPE primers for a specific gene; reaction buffer (for the Ms-SNuPE reaction); and detectably-labeled nucleotides. Additionally, bisulfite conversion reagents may include: DNA denaturation buffer; sulfonation buffer; DNA recovery regents or kit (e.g., precipitation, ultrafiltration, affinity column); desulfonation buffer; and DNA recovery components.

[0441] Additional methylation detection methods include, but are not limited to, methylated CpG island amplification (see, Toyota et al., Cancer Res. 59:2307-12 (1999)) and those described in, e.g., U.S. Patent Publication 2005/0069879; Rein, et al. Nucleic Acids Res. 26 (10): 2255-64 (1998); Olek, et al. Nat. Genet. 17(3): 275-6 (1997); and PCT Publication No. WO 00/70090.

[0442] More detailed information in relation to several of these generally described methods is provided below:

(a) Probe or Primer Design and/or Production

[0443] Several methods described herein for the diagnosis of a neoplasia use one or more probes and/or primers. Methods for designing probes and/or primers for use in, for example, PCR or hybridization are known in the art and described, for example, in Dieffenbach and Dveksler (Eds) (In: PCR Primer: A Laboratory Manual, Cold Spring Harbor Laboratories, NY, 1995). Furthermore, several software packages are publicly available that design optimal probes and/or primers for a variety of assays, e.g. Primer 3 available from the Center for Genome Research, Cambridge, Mass., USA.

[0444] Clearly, the potential use of the probe or primer should be considered during its design. For example, should the probe or primer be produced for use in a methylation specific PCR or ligase chain reaction (LCR) assay the nucleotide at the 3' end (or 5' end in the case of LCR) should preferably correspond to a methylated nucleotide in a nucleic acid.

[0445] Probes and/or primers useful for detection of a sequence associated with a neoplasia are assessed, for example, to determine those that do not form hairpins, self-prime or form primer dimers (e.g. with another probe or primer used in a detection assay). Furthermore, a probe or primer (or the sequence thereof) is often assessed to determine the temperature at which it denatures from a target nucleic acid (i.e. the melting temperature of the probe or primer, or Tm). Methods for estimating Tm are known in the art and described, for example, in Santa Lucia, Proc. Natl. Acad. Sci. USA, 95: 1460-1465, 1995 or Bresslauer et al., Proc. Natl. Acad. Sci. USA, 83: 3746-3750, 1986.

[0446] Methods for producing/synthesizing a probe or primer of the present invention are known in the art. For example, oligonucleotide synthesis is described, in Gait (Ed) (In: Oligonucleotide Synthesis: A Practical Approach, IRL Press, Oxford, 1984). For example, a probe or primer may be obtained by biological synthesis (e.g. by digestion of a nucleic acid with a restriction endonuclease) or by chemical synthesis. For short sequences (up to about 100 nucleotides) chemical synthesis is preferable.

[0447] For longer sequences standard replication methods employed in molecular biology are useful, such as, for example, the use of M13 for single stranded DNA as described by Messing, Methods Enzymol, 101, 20-78, 1983. Other methods for oligonucleotide synthesis include, for example, phosphotriester and phosphodiester methods (Narang, et al. Meth. Enzymol 68: 90, 1979) and synthesis on a support (Beaucage, et al. Tetrahedron Letters 22:1859-1862, 1981) as well as phosphoramidate technique, Caruthers, M. H., et al., Methods in Enzymology, Vol. 154, pp. 287-314 (1988), and others described in "Synthesis and Applications of DNA and RNA," S. A. Narang, editor, Academic Press, New York, 1987, and the references cited therein. Probes comprising locked nucleic acid (LNA) are synthesized as described, for example, in Nielsen et al. J. Chem. Soc. Perkin Trans., 1:3423, 1997; Singh and Wengel, Chem. Commun. 1247, 1998. While, probes comprising peptide-nucleic acid (PNA) are synthesized as described, for example, in Egholm et al., Am. Chem. Soc., 114:1895, 1992; Egholm et al., Nature, 365:566, 1993; and Orum et al., Nucl. Acids Res., 21:5332, 1993.

(b) Methylation-Sensitive Endonuclease Digestion of DNA

[0448] In one example, the increased methylation in a sample is determined using a process comprising treating the nucleic acid with an amount of a methylation-sensitive restriction endonuclease enzyme under conditions sufficient for nucleic acid to be digested and then detecting the fragments produced. Exemplary methylation-sensitive endonucleases include, for example, HhaI or HpaII. Preferably, assays include internal controls that are digested with a methylation-insensitive enzyme having the same specificity as the methylation-sensitive enzyme employed. For example, the methylation-insensitive enzyme MspI is an isoschizomer of the methylation-sensitive enzyme HpaII.

Hybridization Assay Formats

[0449] In one example, the digestion of nucleic acid is detected by selective hybridization of a probe or primer to the undigested nucleic acid. Alternatively, the probe selectively hybridizes to both digested and undigested nucleic acid but facilitates differentiation between both forms, e.g., by electrophoresis. Suitable detection methods for achieving selective hybridization to a hybridization probe include, for example, Southern or other nucleic acid hybridization (Kawai et al., Mol. Cell. Biol. 14:7421-7427, 1994; Gonzalgo et al., Cancer Res. 57:594-599, 1997).

[0450] Suitable hybridization conditions are determined based on the melting temperature (Tm) of a nucleic acid duplex comprising the probe. The skilled artisan will be aware that optimum hybridization reaction conditions should be determined empirically for each probe, although some generalities can be applied. Preferably, hybridizations employing short oligonucleotide probes are performed at low to medium stringency. In the case of a GC rich probe or primer or a longer probe or primer a high stringency hybridization and/or wash is preferred. A high stringency is defined herein as being a hybridization and/or wash carried out in about 0.1.times.SSC buffer and/or about 0.1% (w/v) SDS, or lower salt concentration, and/or at a temperature of at least 65.degree. C., or equivalent conditions. Reference herein to a particular level of stringency encompasses equivalent conditions using wash/hybridization solutions other than SSC known to those skilled in the art.

[0451] In accordance with the present example, a difference in the fragments produced for the test sample and a negative control sample is indicative of the subject having a neoplasia. Similarly, in cases where the control sample comprises data from a tumor, cancer tissue or a cancerous cell or pre-cancerous cell, similarity, albeit not necessarily absolute identity, between the test sample and the control sample is indicative of a positive diagnosis (i.e. cancer).

Amplification Assay Formats

[0452] In an alternative example, the fragments produced by the restriction enzyme are detected using an amplification system, such as, for example, polymerase chain reaction (PCR), rolling circle amplification (RCA), inverse polymerase chain reaction (iPCR), in situ PCR (Singer-Sam et al., Nucl. Acids Res. 18:687, 1990), strand displacement amplification (SDA) or cycling probe technology.

[0453] Methods of PCR are known in the art and described, for example, by McPherson et al., PCR: A Practical Approach. (series eds, D. Rickwood and B. D. Hames), IRL Press Limited, Oxford. pp 1-253, 1991 and by Dieffenbach (ed) and Dveksler (ed) (In: PCR Primer: A Laboratory Manual, Cold Spring Harbour Laboratories, NY, 1995), the contents of which are each incorporated in their entirety by way of reference. Generally, for PCR two non-complementary nucleic acid primer molecules comprising at least about 18 nucleotides in length, and more preferably at least 20-30 nucleotides in length are hybridized to different strands of a nucleic acid template molecule at their respective annealing sites, and specific nucleic acid molecule copies of the template that intervene the annealing sites are amplified enzymatically. Amplification products may be detected, for example, using electrophoresis and detection with a detectable marker that binds nucleic acids. Alternatively, one or more of the oligonucleotides are labeled with a detectable marker (e.g. a fluorophore) and the amplification product detected using, for example, a lightcycler (Perkin Elmer, Wellesley, Mass., USA, Roche Applied Science, Indianapolis, Ind., USA).

[0454] Strand displacement amplification (SDA) utilizes oligonucleotide primers, a DNA polymerase and a restriction endonuclease to amplify a target sequence. The oligonucleotides are hybridized to a target nucleic acid and the polymerase is used to produce a copy of the region intervening the primer annealing sites. The duplexes of copied nucleic acid and target nucleic acid are then nicked with an endonuclease that specifically recognizes a sequence at the beginning of the copied nucleic acid. The DNA polymerase recognizes the nicked DNA and produces another copy of the target region at the same time displacing the previously generated nucleic acid. The advantage of SDA is that it occurs in an isothermal format, thereby facilitating high-throughput automated analysis.

[0455] Cycling Probe Technology uses a chimeric synthetic primer that comprises DNA-RNA-DNA that is capable of hybridizing to a target sequence. Upon hybridization to a target sequence the RNA-DNA duplex formed is a target for RNaseH thereby cleaving the primer. The cleaved primer is then detected, for example, using mass spectrometry or electrophoresis.

[0456] For primers that flank or are adjacent to a methylation-sensitive endonuclease recognition site, it is preferred that such primers flank only those sites that are hypermethylated in neoplasia to ensure that a diagnostic amplification product is produced. In this regard, an amplification product will only be produced when the restriction site is not cleaved, i.e., when it is methylated. Accordingly, detection of an amplification product indicates that the CpG dinucleotide/s of interest is/are methylated.

[0457] As will be known to the skilled artisan, the precise length of the amplified product will vary depending upon the distance between the primers. Clearly this form of analysis may be used to determine the methylation status of a plurality of CpG dinucleotides provided that each dinucleotide is within a methylation sensitive restriction endonuclease site. In these methods, one or more of the primers may be labeled with a detectable marker to facilitate rapid detection of amplified nucleic acid, for example, a fluorescent label (e.g. Cy5 or Cy3) or a radioisotope (e.g. .sup.32P).

[0458] The amplified nucleic acids are generally analyzed using, for example, non-denaturing agarose gel electrophoresis, non-denaturing polyacrylamide gel electrophoresis, mass spectrometry, liquid chromatography (e.g. HPLC or dHPLC), or capillary electrophoresis. (e.g. MALDI-TOF). High throughput detection methods, such as, for example, matrix-assisted laser desorption/ionization time of flight (MALDI-TOF), electrospray ionization (ESI), mass spectrometry (including tandem mass spectrometry, e.g. LC MS/MS), biosensor technology, evanescent fiber-optics technology or DNA chip technology (e.g., WO98/49557; WO 96/17958; Fodor et al., Science 767-773, 1991; U.S. Pat. Nos. 5,143,854; and 5,837,832, the contents of which are all incorporated herein by reference), are especially preferred for all assay formats described herein. Alternatively, amplification of a nucleic acid may be continuously monitored using a melting curve analysis method as described herein and/or in, for example, U.S. Pat. No. 6,174,670, which is incorporated herein by reference.

(c) Other Assay Formats

[0459] In an alternative example, the increased methylation in a sample is determined by performing a process comprising treating chromatin containing the nucleic acid with an amount of DNaseI under conditions sufficient for nucleic acid to be digested and then detecting the fragments produced. This assay format is predicated on the understanding that chromatin containing methylated DNA, e.g., hyper methylated DNA, has a more tightly-closed conformation than non-hyper methylated DNA and, as a consequence, is less susceptible to endonuclease digestion by DNase I.

[0460] In accordance with this method , DNA fragments of different lengths are produced by DNase I digestion of methylated compared to non-methylated DNA. Such different DNA fragments are detected, for example, using an assay described earlier. Alternatively, the DNA fragments are detected using PCR-SSCP essentially as described, for example, in Gregory and Feil, Nucleic Acids Res., 27, e32i-e32iv, 1999. In adapting PCR-SSCP to the present invention, amplification primers flanking or comprising one or more CpG dinucleotides in a nucleic acid that are resistant to DNase I digestion in a neoplasia sample but not resistant to DNase I digestion in a healthy/normal control or healthy/normal test sample are used to amplify the DNase I-generated fragments. In this case, the production of a specific nucleic acid fragment using DNase I is diagnostic of neoplasia, because the DNA is not efficiently degraded. In contrast, template DNA from a healthy/normal subject sample is degraded by the action of DNase I and, as a consequence, amplification fails to produce a discrete amplification product. Alternative methods to PCR-SSCP, such as for example, PCR-dHPLC are also known in the art and contemplated by the present invention.

(d) Selective Mutagenesis of Non Methylated DNA

[0461] In an alternative method the increased methylation in a sample is determined using a process comprising treating the nucleic acid with an amount of a compound that selectively mutates a non-methylated cytosine residue within a CpG dinucleotide under conditions sufficient to induce mutagenesis.

[0462] Preferred compounds mutate cytosine to uracil or thymidine, such as, for example, a salt of bisulfite, e.g., sodium bisulfite or potassium bisulfite (Frommer et al., 1992, supra). Bisulfite treatment of DNA is known to distinguish methylated from non-methylated cytosine residues, by mutating cytosine residues that are not protected by methylation, including cytosine residues that are not within a CpG dinucleotide or that are positioned within a CpG dinucleotide that is not subject to methylation.

Sequence Based Detection

[0463] In one example, the presence of one or more mutated nucleotides or the number of mutated sequences is determined by sequencing mutated DNA. One form of analysis comprises amplifying mutated nucleic acid using an amplification reaction described herein, for example, PCR. The amplified product is then directly sequenced or cloned and the cloned product sequenced. Methods for sequencing DNA are known in the art and include for example, the dideoxy chain termination method or the Maxam-Gilbert method (see Sambrook et al., Molecular Cloning, A Laboratory Manual (2nd Ed., CSHP, New York 1989) or Zyskind et al., Recombinant DNA Laboratory Manual, (Acad. Press, 1988)).

[0464] As the treatment of nucleic acid with a compound, such as, for example, bisulfite results in non-methylated cytosines being mutated to uracil (and hence thymidine after an amplification process), analysis of the sequence determines the presence or absence of a methylated nucleotide. For example, by comparing the sequence obtained using a control sample or a sample that has not been treated with bisulfite, or the known nucleotide sequence of the region of interest with a treated sample facilitates the detection of differences in the nucleotide sequence. Any thymine residue detected at the site of a cytosine in the treated sample compared to a control or untreated sample may be considered to be caused by mutation as a result of bisulfite treatment. Suitable methods for the detection of methylation using sequencing of bisulfite treated nucleic acid are described, for example, in Frommer et al., 1992, supra or Clark et al., Nucl. Acids Res. 22:2990-2997, 1994.

[0465] In another method, the presence of a mutated or non-mutated nucleotide in a bisulfite treated sample is detected using pyrosequencing, such as, for example, as described in Uhlmann et al., Electrophoresis, 23: 4072-4079, 2002. Essentially this method is a form of real-time sequencing that uses a primer that hybridizes to a site adjacent or close to the site of a cytosine that is methylated. Following hybridization of the primer and template in the presence of a DNA polymerase each of four modified deoxynucleotide triphosphates are added separately according to a predetermined dispensation order. Only an added nucleotide that is complementary to the bisulfite treated sample is incorporated and inorganic pyrophosphate (PPi) is liberated. The PPi then drives a reaction resulting in production of detectable levels of light. Such a method allows determination of the identity of a specific nucleotide adjacent to the site of hybridization of the primer.

[0466] Methods of solid phase pyrosequencing are known in the art and reviewed in, for example, Landegren et al., Genome Res., 8(8): 769-776, 1998. Such methods enable the high-throughput detection of methylation of a number of CpG dinucleotides.

[0467] A related method for determining the sequence of a bisulfite treated nucleotide is methylation-sensitive single nucleotide primer extension (Me-SnuPE) or SNaPmeth. Suitable methods are described, for example, in Gonzalgo and Jones, 1997, supra, or Uhlmann et al., Electrophoresis, 23:4072-4079, 2002. An oligonucleotide is used that hybridizes to the region of a nucleic acid adjacent to the site of a cytosine that is methylated. This oligonucleotide is then used in a primer extension protocol with a polymerase and a free nucleotide diphosphate or dideoxynucleotide triphosphate that corresponds to either or any of the possible bases that occur at this site following bisulfite treatment (i.e., thymine or cytosine). Preferably, the nucleotide-diphosphate is labeled with a detectable marker (e.g. a fluorophore). Following primer extension, unbound labeled nucleotide diphosphates are removed, e.g. using size exclusion chromatography or electrophoresis, or hydrolyzed, using for example, alkaline phosphatase, and the incorporation of the labeled nucleotide to the oligonucleotide is detected, indicating the base that is present at the site.

[0468] Clearly other high throughput sequencing methods are encompassed by the present invention. Such methods include, for example, solid phase minisequencing (as described, for example, in Southern et al., Genomics, 13:1008-1017, 1992), or minisequencing with FRET (as described, for example, in Chen and Kwok, Nucleic Acids Res. 25:347-353, 1997).

Restriction Endonuclease-Based Assay Format

[0469] In one method, the presence of a non-mutated sequence is detected using combined bisulfite restriction analysis (COBRA) essentially as described in Xiong and Laird, 2001, supra. This method exploits the differences in restriction enzyme recognition sites between methylated and unmethylated nucleic acid after treatment with a compound that selectively mutates a non-methylated cytosine residue, e.g., bisulfite.

[0470] Following bisulfite treatment a region of interest comprising one or more CpG dinucleotides that are methylated and are included in a restriction endonuclease recognition sequence is amplified using an amplification reaction described herein, e.g., PCR. The amplified product is then contacted with the restriction enzyme that cleaves at the site of the CpG dinucleotide for a time and under conditions sufficient for cleavage to occur. A restriction site may be selected to indicate the presence or absence of methylation. For example, the restriction endonuclease TaqI cleaves the sequence TCGA, following bisulfite treatment of a non-methylated nucleic acid the sequence will be TTGA and, as a consequence, will not be cleaved. The digested and/or non-digested nucleic acid is then detected using a detection means known in the art, such as, for example, electrophoresis and/or mass spectrometry. The cleavage or non-cleavage of the nucleic acid is indicative of cancer in a subject. Clearly, this method may be employed in either a positive read-out or negative read-out system for the diagnosis of a cancer.

Positive Read-Out Assay Format

[0471] In one embodiment, the assay format of the invention comprises a positive read-out system in which DNA from a sample that has been treated, for example, with bisulfite is detected as a positive signal. Preferably, the non-hypermethylated DNA from a healthy or normal control subject is not detected or only weakly detected.

[0472] In a preferred embodiment, the increased methylation in a subject sample is determined using a process comprising:

[0473] (i) treating the nucleic acid with an amount of a compound that selectively mutates a non-methylated cytosine residue under conditions sufficient to induce mutagenesis thereby producing a mutated nucleic acid;

[0474] (ii) hybridizing a nucleic acid to a probe or primer comprising a nucleotide sequence that is complementary to a sequence comprising a methylated cytosine residue under conditions such that selective hybridization to the non-mutated nucleic acid occurs; and

[0475] (iii) detecting the selective hybridization.

[0476] In this context, the term "selective hybridization" means that hybridization of a probe or primer to the non-mutated nucleic acid occurs at a higher frequency or rate, or has a higher maximum reaction velocity, than hybridization of the same probe or primer to the corresponding mutated sequence. Preferably, the probe or primer does not hybridize to the non-methylated sequence carrying the mutation(s) under the reaction conditions used.

Hybridization-Based Assay Format

[0477] In one embodiment, the hybridization is detected using Southern, dot blot, slot blot or other nucleic acid hybridization means (Kawai et al., 1994, supra; Gonzalgo et al., 1997, supra). Subject to appropriate probe selection, such assay formats are generally described herein above and apply mutatis mutandis to the presently described selective mutagenesis approach.

[0478] Preferably, a ligase chain reaction format is employed to distinguish between a mutated and non-mutated nucleic acid. Ligase chain reaction (described in EP 320,308 and U.S. Pat. No. 4,883,750) uses at least two oligonucleotide probes that anneal to a target nucleic acid in such a way that they are juxtaposed on the target nucleic acid. In a ligase chain reaction assay, the target nucleic acid is hybridized to a first probe that is complementary to a diagnostic portion of the target sequence (the diagnostic probe) e.g., a nucleic acid comprising one or more methylated CpG dinucleotide(s), and with a second probe that is complementary to a nucleotide sequence contiguous with the diagnostic portion (the contiguous probe), under conditions wherein the diagnostic probe remains bound substantially only to the target nucleic acid. The diagnostic and contiguous probes can be of different lengths and/or have different melting temperatures such that the stringency of the hybridization can be adjusted to permit their selective hybridization to the target, wherein the probe having the higher melting temperature is hybridized at higher stringency and, following washing to remove unbound and/or non-selectively bound probe, the other probe having the lower melting temperature is hybridized at lower stringency. The diagnostic probe and contiguous probe are then covalently ligated such as, for example, using T4 DNA ligase, to thereby produce a larger target probe that is complementary to the target sequence, and the probes that are not ligated are removed by modifying the hybridization stringency. In this respect, probes that have not been ligated will selectively hybridize under lower stringency hybridization conditions than probes that have been ligated. Accordingly, the stringency of the hybridization can be increased to a stringency that is at least as high as the stringency used to hybridize the longer probe, and preferably at a higher stringency due to the increased length contributed by the shorter probe following ligation.

[0479] In another example, one or both of the probes is labeled such that the presence or absence of the target sequence can be tested by melting the target-probe duplex, eluting the dissociated probe, and testing for the label(s). Where both probes are labeled, different ligands are used to permit distinction between the ligated and unligated probes, in which case the presence of both labels in the same eluate fraction confirms the ligation event. If the target nucleic acid is bound to a solid matrix e.g., in a Southern hybridization, slot blot, dot blot, or microchip assay format, the presence of both the diagnostic and contiguous probes can be determined directly.

[0480] Methylation specific microarrays (MSO) are also useful for differentiating between a mutated and non-mutated sequence. A suitable method is described, for example, in Adorjan et al. Nucl. Acids Res., 30: e21, 2002. MSO uses nucleic acid that has been treated with a compound that selectively mutates a non-methylated cytosine residue (e.g., bisulfite) as template for an amplification reaction that amplifies both mutant and non-mutated nucleic acid. The amplification is performed with at least one primer that comprises a detectable label, such as, for example, a fluorophore, e.g., Cy3 or Cy5.

[0481] To produce a microarray for detection of mutated nucleic acid oligonucleotides are spotted onto, for example, a glass slide, preferably, with a degree of redundancy (for example, as described in Golub et al., Science, 286:531-537, 1999). Preferably, for each CpG dinucleotide analyzed two different oligonucleotides are used. Each oligonucleotide comprises a sequence N.sub.2-16CGN.sub.2-16 or N.sub.2-16TGN.sub.2-16 (wherein N is a number of nucleotides adjacent or juxtaposed to the CpG dinucleotide of interest) reflecting the methylated or non-methylated status of the CpG dinucleotides.

[0482] The labeled amplification products are then hybridized to the oligonucleotides on the microarray under conditions that enable detection of single nucleotide differences. Following washing to remove unbound amplification product, hybridization is detected using, for example, a microarray scanner. Not only does this method allow for determination of the methylation status of a large number of CpG dinucleotides, it is also semi-quantitative, enabling determination of the degree of methylation at each CpG dinucleotide analyzed. As there may be some degree of heterogeneity of methylation in a single sample, such quantification may assist in the diagnosis of cancer.

Amplification-Based Assay Format

[0483] In an alternative example, the hybridization is detected using an amplification system. In methylation-specific PCR formats (MSP; Herman et al. Proc. Natl. Acad. Sci. USA 93:9821-9826, 1992), the hybridization is detected using a process comprising amplifying the bisulfite-treated DNA. Accordingly, by using one or more probe or primer that anneals specifically to the unmutated sequence under moderate and/or high stringency conditions an amplification product is only produced using a sample comprising a methylated nucleotide. Alternate assays that provide for selective amplification of either the methylated or the unmethylated component from a mixture of bisulfite-treated DNA are provided by Cottrell et al., Nucl. Acids Res. 32: e10, 2003 (HeavyMethyl PCR), Rand et al. Nucl. Acids Res. 33:e127, 2005 (Headloop PCR), Rand et al. Epigenetics 1:94-100, 2006 (Bisulfite Differential Denaturation PCR) and PCT/AU07/000389 (End-specific PCR).

[0484] Any amplification assay format described herein can be used, such as, for example, polymerase chain reaction (PCR), rolling circle amplification (RCA), inverse polymerase chain reaction (iPCR), in situ PCR (Singer-Sam et al., 1990, supra), strand displacement amplification, or cycling probe technology. PCR techniques have been developed for detection of gene mutations (Kuppuswamy et al., Proc. Natl. Acad. Sci. USA 88:1143-1147, 1991) and quantitation of allelic-specific expression (Szabo and Mann, Genes Dev. 9: 3097-3108, 1995; and Singer-Sam et al., PCR Methods Appl. 1: 160-163, 1992). Such techniques use internal primers, which anneal to a PCR-generated template and terminate immediately 5' of the single nucleotide to be assayed. Such as format is readily combined with ligase chain reaction as described herein above. The use of a real-time quantitative assay format is also useful. Subject to the selection of appropriate primers, such assay formats are generally described herein above and apply mutatis mutandis to the presently described selective mutagenesis approach.

[0485] Methylation-specific melting-curve analysis (essentially as described in Worm et al., Clin. Chem., 47:1183-1189, 2001) is also contemplated by the present invention. This process exploits the difference in melting temperature in amplification products produced using bisulfite treated methylated or unmethylated nucleic acid. In essence, non-discriminatory amplification of a bisulfite treated sample is performed in the presence of a fluorescent dye that specifically binds to double stranded DNA (e.g., SYBR Green I). By increasing the temperature of the amplification product while monitoring fluorescence the melting properties and thus the sequence of the amplification product is determined. A decrease in the fluorescence reflects melting of at least a domain in the amplification product. The temperature at which the fluorescence decreases is indicative of the nucleotide sequence of the amplified nucleic acid, thereby permitting the nucleotide at the site of one or more CpG dinucleotides to be determined. As the sequence of the nucleic acids amplified using the present invention

[0486] The present invention also encompasses the use of real-time quantitative forms of PCR, such as, for example, TaqMan (Holland et al., Proc. Natl. Acad. Sci. USA, 88:7276-7280, 1991; Lee et al., Nucleic Acid Res. 21:3761-3766, 1993) to perform this embodiment. For example, the MethylLight method of Eads et al., Nucl. Acids Res. 28: E32, 2000 uses a modified TaqMan assay to detect methylation of a CpG dinucleotide. Essentially, this method comprises treating a nucleic acid sample with bisulfite and amplifying nucleic acid comprising one or more CpG dinucleotides that are methylated in a neoplastic cell and not in a control sample using an amplification reaction, e.g., PCR. The amplification reaction is performed in the presence of three oligonucleotides, a forward and reverse primer that flank the region of interest and a probe that hybridizes between the two primers to the site of the one or more methylated CpG dinucleotides. The probe is dual labeled with a 5' fluorescent reporter and a 3' quencher (or vice versa). When the probe is intact, the quencher dye absorbs the fluorescence of the reporter due to their proximity. Following annealing of to the PCR product the probe is cleaved by 5' to 3' exonuclease activity of, for example, Taq DNA polymerase. This cleavage releases the reporter from the quencher thereby resulting in an increased fluorescence signal that can be used to estimate the initial template methylation level. By using a probe or primer that selectively hybridizes to unmutated nucleic acid (i.e. methylated nucleic acid) the level of methylation is determined, e.g., using a standard curve.

[0487] Alternatively, rather than using a labeled probe that requires cleavage, a probe, such as, for example, a Molecular Beacon is used (see, for example, Mhlanga and Malmberg, Methods 25:463-471, 2001). Molecular beacons are single stranded nucleic acid molecules with a stem-and-loop structure. The loop structure is complementary to the region surrounding the one or more CpG dinucleotides that are methylated in a neoplastic sample and not in a control sample. The stem structure is formed by annealing two "arms" complementary to each other, which are on either side of the probe (loop). A fluorescent moiety is bound to one arm and a quenching moiety that suppresses any detectable fluorescence when the molecular beacon is not bound to a target sequence is bound to the other arm. Upon binding of the loop region to its target nucleic acid the arms are separated and fluorescence is detectable. However, even a single base mismatch significantly alters the level of fluorescence detected in a sample. Accordingly, the presence or absence of a particular base is determined by the level of fluorescence detected. Such an assay facilitates detection of one or more unmutated sites (i.e. methylated nucleotides) in a nucleic acid.

[0488] Fluorescently labeled locked nucleic acid (LNA) molecules or fluorescently labeled protein-nucleic acid (PNA) molecules are useful for the detection of nucleotide differences (e.g., as described in Simeonov and Nikiforov, Nucleic Acids Research, 30(17):1-5, 2002). LNA and PNA molecules bind, with high affinity, to nucleic acid, in particular, DNA. Fluorophores (in particular, rhodamine or hexachlorofluorescein) conjugated to the LNA or PNA probe fluoresce at a significantly greater level upon hybridization of the probe to target nucleic acid. However, the level of increase of fluorescence is not enhanced to the same level when even a single nucleotide mismatch occurs. Accordingly, the degree of fluorescence detected in a sample is indicative of the presence of a mismatch between the LNA or PNA probe and the target nucleic acid, such as, in the presence of a mutated cytosine in a methylated CpG dinucleotide. Preferably, fluorescently labeled LNA or PNA technology is used to detect at least a single base change in a nucleic acid that has been previously amplified using, for example, an amplification method known in the art and/or described herein.

[0489] As will be apparent to the skilled artisan, LNA or PNA detection technology is amenable to a high-throughput detection of one or more markers by immobilizing an LNA or PNA probe to a solid support, as described in Orum et al., Clin. Chem. 45:1898-1905, 1999.

[0490] Alternatively, a real-time assay, such as, for example, the so-called HeavyMethyl assay (Cottrell et al., 2003, supra) is used to determine the presence or level of methylation of nucleic acid in a test sample. Essentially, this method uses one or more non-extendible nucleic acid (e.g., oligonucleotide) blockers that bind to bisulfite-treated nucleic acid in a methylation specific manner (i.e., the blocker/s bind specifically to unmutated DNA under moderate to high stringency conditions). An amplification reaction is performed using one or more primers that may optionally be methylation specific but that flank the one or more blockers. In the presence of unmethylated nucleic acid (i.e., non-mutated DNA) the blocker/s bind and no PCR product is produced. Using a TaqMan assay essentially as described supra the level of methylation of nucleic acid in a sample is determined.

[0491] Other amplification-based methods for detecting methylated nucleic acid following treatment with a compound that selectively mutates a non-methylated cytosine residue include, for example, methylation-specific single stranded conformation analysis (MS-SSCA) (Bianco et al., Hum. Mutat., 14:289-293, 1999), methylation-specific denaturing gradient gel electrophoresis (MS-DGGE) (Abrams and Stanton, Methods Enzymol., 212:71-74, 1992) and methylation-specific denaturing high-performance liquid chromatography (MS-DHPLC) (Deng et al. Chin. J. Cancer Res., 12:171-191, 2000). Each of these methods use different techniques for detecting nucleic acid differences in an amplification product based on differences in nucleotide sequence and/or secondary structure. Such methods are clearly contemplated by the present invention.

[0492] As with other amplification-based assay formats, the amplification product is analyzed using a range of procedures, including gel electrophoresis, gel filtration, mass spectrometry, and in the case of labeled primers, by identifying the label in the amplification product. In an alternative embodiment, restriction enzyme digestion of PCR products amplified from bisulfite-converted DNA is performed essentially as described by Sadri and Hornsby, Nucl. Acids Res. 24:5058-5059, 1996; and Xiong and Laird, Nucl. Acids Res. 25:2532-2534, 1997), to analyze the product formed.

[0493] High throughput detection methods, such as, for example, matrix-assisted laser desorption/ionization time of flight (MALDI-TOF), electrospray ionization (ESI), Mass spectrometry (including tandem mass spectrometry, e.g. LC MS/MS), biosensor technology, evanescent fiber-optics technology or DNA chip technology, can also be employed.

[0494] As with the other assay formats described herein that utilize hybridization and/or amplification detection systems, combinations of such processes as described herein above are particularly contemplated by the selective mutagenesis-based assay formats of the present invention. In one example, the increased methylation is detected by performing a process comprising:

[0495] (i) treating the nucleic acid with an amount of a compound that selectively mutates a non-methylated cytosine residue within a CpG dinucleotide under conditions sufficient to induce mutagenesis thereby producing a mutated nucleic acid;

[0496] (ii) hybridizing the nucleic acid to two non-overlapping and non-complementary primers each of which comprises a nucleotide sequence that is complementary to a sequence in the DNA comprising a methylated cytosine residue under conditions such that hybridization to the non-mutated nucleic acid occurs;

[0497] (iii) amplifying nucleic acid intervening the hybridized primers thereby producing a DNA fragment consisting of a sequence that comprises a primer sequence;

[0498] (iv) hybridizing the amplified DNA fragment to a probe comprising a nucleotide sequence that corresponds or is complementary to a sequence comprising a methylated cytosine residue under conditions such that hybridization to the non-mutated nucleic acid occurs; and detecting the hybridization.

Negative Read-Out Assays

[0499] In another example, the assay format comprises a negative read-out system in which reduced methylation of DNA from a healthy/normal control sample is detected as a positive signal and preferably, methylated DNA from a neoplastic sample is not detected or is only weakly detected.

[0500] In a preferred embodiment, the reduced methylation is determined using a process comprising:

[0501] (i) treating the nucleic acid with an amount of a compound that selectively mutates a non-methylated cytosine residue within a CpG island under conditions sufficient to induce mutagenesis thereby producing a mutated nucleic acid;

[0502] (ii) hybridizing the nucleic acid to a probe or primer comprising a nucleotide sequence that is complementary to a sequence comprising the mutated cytosine residue under conditions such that selective hybridization to the mutated nucleic acid occurs; and

[0503] (iii) detecting the selective hybridization.

[0504] In this context, the term "selective hybridization" means that hybridization of a probe or primer to the mutated nucleic acid occurs at a higher frequency or rate, or has a higher maximum reaction velocity, than hybridization of the same probe or primer to the corresponding non-mutated sequence. Preferably, the probe or primer does not hybridize to the methylated sequence (or non-mutated sequence) under the reaction conditions used.

Hybridization-Based Assay Format

[0505] In one embodiment the hybridization is detected using Southern, dot blot, slot blot or other nucleic acid hybridization means (Kawai et al., 1994, supra; Gonzalgo et al., 1997, supra). Subject to appropriate probe selection, such assay formats are generally described herein above and apply mutatis mutandis to the presently described selective mutagenesis approach. Preferably, a ligase chain reaction format is employed to distinguish between a non-mutated and mutated nucleic acid. In this respect, the assay requirements and conditions are as described herein above for positive read-out assays and apply mutatis mutandis to the present format. However the selection of probes will differ. For negative read-out assays, one or more probes are selected that selectively hybridize to the mutated sequence rather than the non-mutated sequence.

[0506] Preferably, the ligase chain reaction probe(s) have 3'-terminal and/or 5'-terminal sequences that comprise a CpG dinucleotide that is not methylated in a healthy control sample, but is hypermethylated in cancer, such that the diagnostic probe and contiguous probe are capable of being ligated only when the cytosine of the CpG dinucleotide is mutated to thymidine e.g., in the case of a non-methylated cytosine residue.

[0507] As will be apparent to the skilled artisan the MSO method described supra is amenable to either or both positive and/or negative readout assays. This is because the assay described detects both mutated and non-mutated sequences thereby facilitating determining the level of methylation. However, an assay detecting only methylated or non-methylated sequences is contemplated by the invention.

Amplification-Based Assay Format

[0508] In an alternative example, the hybridization is detected using an amplification system using any amplification assay format as described herein above for positive read-out assay albeit using primers (and probes where applicable) selectively hybridize to a mutated nucleic acid.

[0509] In adapting the HeavyMethyl assay described supra to a negative read-out format, the blockers that bind to bisulfite-treated nucleic acid in a methylation specific manner bind specifically to mutated DNA under moderate to high stringency conditions. An amplification reaction is performed using one or more primers that may optionally be methylation specific (i.e. only bind to mutated nucleic acid) but that flank the one or more blockers. In the presence of methylated nucleic acid (i.e., mutated DNA) the blocker/s bind and no PCR product is produced.

[0510] In one example, the reduced methylation in the normal/healthy control subject is detected by performing a process comprising:

[0511] (i) treating the nucleic acid with an amount of a compound that selectively mutates non-methylated cytosine residues under conditions sufficient to induce mutagenesis thereby producing a mutated nucleic acid;

[0512] (ii) hybridizing the nucleic acid to two non-overlapping and non-complementary primers each of which comprises a nucleotide sequence that is complementary to a sequence in the DNA comprising a mutated cytosine residue under conditions such that hybridization to the mutated nucleic acid occurs;

[0513] (iii) amplifying nucleic acid intervening the hybridized primers thereby producing a DNA fragment consisting of a sequence that comprises a primer sequence;

[0514] (iv) hybridizing the amplified DNA fragment to a probe comprising a nucleotide sequence that corresponds or is complementary to a sequence comprising a mutated cytosine residue under conditions such that hybridization to the mutated nucleic acid occurs; and

[0515] (v) detecting the hybridization.

[0516] As will be apparent to the skilled artisan a negative read-out assay preferably includes a suitable control sample to ensure that the negative result is caused by methylated nucleic acid rather than a reaction failing.

[0517] This invention also provides kits for the detection and/or quantification of the diagnostic sequences of the invention, or expression or methylation thereof using the methods described herein.

[0518] For kits for detection of methylation, the kits of the invention can comprise at least one polynucleotide that hybridizes to at least one of the diagnostic sequences of the invention and at least one reagent for detection of gene methylation. Reagents for detection of methylation include, e.g., sodium bisulfite, polynucleotides designed to hybridize to sequence that is the product of a biomarker sequence of the invention if the biomarker sequence is not methylated (e.g., containing at least one C.fwdarw.U conversion), and/or a methylation-sensitive or methylation-dependent restriction enzyme. The kits may also include control natural or synthetic DNA sequences representing methylated or unmethylated forms of the sequence. The kits can provide solid supports in the form of an assay apparatus that is adapted to use in the assay. The kits may further comprise detectable labels, optionally linked to a polynucleotide, e.g., a probe, in the kit. Other materials useful in the performance of the assays can also be included in the kits, including test tubes, transfer pipettes, and the like. The kits can also include written instructions for the use of one or more of these reagents in any of the assays described herein.

[0519] As detailed hereinbefore, hypermethylation is associated with transcriptional silencing. Accordingly, in addition to the increased level of methylation of these genes providing a basis upon which to screen for the predisposition to or onset of a large intestine neoplasm, the downregulation in the level of expression of these genes is also diagnostically valuable. In accordance with this aspect of the present invention, reference to a gene "expression product" or "expression of a gene" is a reference to either a transcription product (such as primary RNA or mRNA) or a translation product such as protein. In this regard, one can assess changes to the level of expression of a gene either by screening for changes to the level of expression product which is produced (i.e. RNA or protein), changes to the chromatin proteins with which the gene is associated, for example the presence of histone H3 methylated on lysine at amino acid position number 9 or 27 (repressive modifications) or changes to the DNA itself which acts to downregulate expression, such as changes to the methylation of the DNA. These genes and their gene expression products, whether they be RNA transcripts, changes to the DNA which act to downregulate expression or encoded proteins, are collectively referred to as "neoplastic markers".

[0520] Accordingly, another aspect of the present invention is directed to a method of screening for the onset or predisposition to the onset of or monitoring a large intestine neoplasm in an individual, said method comprising assessing the level of expression of a DNA region selected from:

[0521] (i) the region, including 2 kb upstream of the transcription start site, defined by any two or more of Hg19 coordinates:

[0522] (1) chr12:24962958..25102393

[0523] (2) chr7:50344378...50472798

[0524] (3) chr6:391739..411443; or

[0525] (4) chr12:52400748..52409671; and

[0526] (5) chr6:163834097..163834982; or

[0527] (ii) the gene region, including 2 kb upstream of any two or more of:

[0528] (1) BCAT1 (2) IKZF1 (3) IRF4 (4) GRASP and (5) CAHM in a biological sample from said individual wherein a lower level of expression of at least one of the DNA regions of group (i) and/or (ii) relative to control levels is indicative of a large intestine neoplasm or a predisposition to the onset of a neoplastic state.

[0529] In one embodiment, said method is directed to identifying biological samples in which any one of said DNA regions exhibits a higher level of methylation.

[0530] In another embodiment, said method is directed to identifying biological samples in which two or more of said DNA regions exhibits a higher level of methylation.

[0531] The method of this aspect of the present invention is predicated on the comparison of the level of the neoplastic markers of a biological sample with the control levels of these markers. The "control level" may be either a "normal level", which is the level of marker expressed by a corresponding large intestine cell or cellular population which is not neoplastic.

[0532] As detailed hereinbefore, the normal (or "non-neoplastic") level may be determined using tissues derived from the same individual who is the subject of testing. However, it would be appreciated that this may be quite invasive for the individual concerned and it is therefore likely to be more convenient to analyze the test results relative to a standard result which reflects individual or collective results obtained from individuals other than the patient in issue.

[0533] There is more particularly provided a method of screening for the onset or predisposition to the onset of or monitoring a large intestine neoplasm in an individual, said method comprising assessing the level of expression of one or more genes or transcripts selected from:

[0534] (i) the DNA regions, including 2 kb upstream of the transcription start site, defined by Hg19 coordinates:

[0535] (1) chr12:24962958..25102393; and

[0536] (2) chr7:50344378...50472798;

[0537] and optionally one or more of (3) chr6:391739..411443, (4) chr12:52400748..52409671 and (5) chr6:163834097..163834982; or

[0538] (ii) the gene region, including 2 kb upstream or:

[0539] (1) BCAT1; and

[0540] (2) IKZF1;

[0541] and optionally one or more of (3) IRF4, (4) GRASP and (5) CAHM in a biological sample from said individual wherein a lower level of expression of at least one of the DNA regions of group (i) and/or group (ii) relative to control levels is indicative of a neoplastic large intestine neoplasm or a predisposition to the onset of a neoplastic state.

[0542] Preferably, said control level is a non-neoplastic level.

[0543] In one embodiment of this aspect, the gene marker panel which is screened for is:

[0544] (i) the DNA regions, including 2 kb upstream of the transcription start site, defined by Hg19 coordinates:

[0545] (1) chr12:24962958..25102393

[0546] (2) chr7:50344378...50472798; and

[0547] (3) chr6:391739..411443; or

[0548] (ii) the gene region, including 2 kb upstream of:

[0549] (1) BCATI (2) IKZF1 and (3) IRF4

[0550] In another embodiment of this aspect, the gene marker panel which is screened for is:

[0551] (i) the DNA regions, including 2 kb upstream of the transcription start site, defined by Hg19 coordinates:

[0552] (1) chr12:24962958..25102393

[0553] (2) chr7:50344378...50472798; and

[0554] (4) chr12:52400748..52409671; or

[0555] (ii) the gene region, including 2 kb upstream of:

[0556] (1) BCAT1 (2) IKZF1 and (4) GRASP.

[0557] In still another embodiment of this aspect, the gene marker panel which is screened for is:

[0558] (i) the DNA regions, including 2 kb upstream of the transcription start site, defined by Hg19 coordinates:

[0559] (1) chr12:24962958..25102393

[0560] (2) chr7:50344378...50472798; and

[0561] (5) chr6:163834097..163834982; or

[0562] (ii) the gene region, including 2 kb upstream of:

[0563] (1) BCAT1 (2) IKZF1 and (5) CAHM

[0564] In still yet another embodiment of this aspect, the gene marker panel which is screened for is:

[0565] (i) the DNA regions, including 2 kb upstream of the transcription start site, defined by Hg19 coordinates:

[0566] (1) chr12:24962958..25102393

[0567] (2) chr7:50344378...50472798

[0568] (3) chr6:391739..411443; and

[0569] (4) chr12:52400748..52409671; or

[0570] (ii) the gene region, including 2 kb upstream of:

[0571] (1) BCAT1 (2) IKZF1 (3) IRF4 and (4) GRASP

[0572] In yet still another embodiment of this aspect, the gene marker panel which is screened for is:

[0573] (i) the DNA regions, including 2 kb upstream of the transcription start site, defined by Hg19 coordinates:

[0574] (1) chr12:24962958..25102393

[0575] (2) chr7:50344378...50472798

[0576] (3) chr6:391739..411443; and

[0577] (5) chr6:163834097..163834982; or

[0578] (ii) the gene region, including 2 kb upstream of:

[0579] (1) BCAT1 (2) IKZF1 (3) IRF4 and (5) CAHM.

[0580] In a further embodiment of this aspect, the gene marker panel which is screened for is:

[0581] (i) the DNA regions, including 2 kb upstream of the transcription start site, defined by Hg19 coordinates:

[0582] (1) chr12:24962958..25102393

[0583] (2) chr7:50344378...50472798

[0584] (4) chr12:52400748..52409671; and

[0585] (5) chr6:163834097..163834982; or

[0586] (ii) the gene region, including 2 kb upstream of any one or more of:

[0587] (1) BCAT1 (2) IKZF1 (4) GRASP and (5) CAHM

[0588] In yet another further embodiment of this aspect, the gene marker panel which is screened for is:

[0589] (i) the DNA regions, including 2 kb upstream of the transcription start site, defined by Hg19 coordinates:

[0590] (1) chr12:24962958..25102393

[0591] (2) chr7:50344378...50472798

[0592] (3) chr6:391739..411443; or

[0593] (4) chr12:52400748..52409671; and

[0594] (5) chr6:163834097..163834982; or

[0595] (ii) the gene region, including 2 kb upstream of any one or more of:

[0596] (1) BCAT1 (2) IKZF1 (3) IRF4 (4) GRASP and (5) CAHM.

[0597] In one embodiment, said method is directed to identifying biological samples in which any one of said DNA regions exhibits a higher level of methylation.

[0598] In another embodiment, said method is directed to identifying biological samples in which two or more of said DNA regions exhibits a higher level of methylation.

[0599] As detailed hereinbefore, the present invention is designed to screen for a neoplastic cell or cellular population, which is located in the large intestine. Accordingly, reference to "cell or cellular population" should be understood as a reference to an individual cell or a group of cells. Said group of cells may be a diffuse population of cells, a cell suspension, an encapsulated population of cells or a population of cells which take the form of tissue.

[0600] Reference to "expression" should be understood as a reference to the transcription and/or translation of a nucleic acid molecule. Reference to "RNA" should be understood to encompass reference to any form of RNA, such as primary RNA or mRNA or non-translated RNA (e.g. miRNAs etc.). Without limiting the present invention in any way, the modulation of gene transcription leading to increased or decreased RNA synthesis may also correlate with the translation of some of these RNA transcripts (such as mRNA) to produce a protein product. Accordingly, the present invention also extends to detection methodology which is directed to screening for modulated levels or patterns of the neoplastic marker protein products as an indicator of the neoplastic state of a cell or cellular population. Although one method is to screen for mRNA transcripts and/or the corresponding protein product, it should be understood that the present invention is not limited in this regard and extends to screening for any other form of neoplastic marker expression product such as, for example, a primary RNA transcript.

[0601] In terms of screening for the downregulation of expression of a marker it would also be well known to the person of skill in the art that changes which are detectable at the DNA level are indicative of changes to gene expression activity and therefore changes to expression product levels. Such changes include but are not limited to, changes to DNA methylation. Accordingly, reference herein to "screening the level of expression" and comparison of these "levels of expression" to control "levels of expression" should be understood as a reference to assessing DNA factors which are related to transcription, such as gene/DNA methylation patterns. These have, in part, been described in detail hereinbefore.

[0602] It would also be known to a person skilled in the art that changes in the structure of chromatin are indicative of changes in gene expression. Silencing of gene expression is often associated with modification of chromatin proteins, methylation of lysines at either or both positions 9 and 27 of histone H3 being well studied examples, while active chromatin is marked by acetylation of lysine 9 of histone H3. Thus association of gene sequences with chromatin carrying repressive or active modifications can be used to make an assessment of the expression level of a gene.

[0603] Reference to "nucleic acid molecule" should be understood as a reference to both deoxyribonucleic acid molecules and ribonucleic acid molecules and fragments thereof. The present invention therefore extends to both directly screening for mRNA levels in a biological sample or screening for the complementary cDNA which has been reverse-transcribed from an mRNA population of interest. It is well within the skill of the person of skill in the art to design methodology directed to screening for either DNA or RNA. As detailed above, the method of the present invention also extends to screening for the protein product translated from the subject mRNA or the genomic DNA itself.

[0604] In one preferred embodiment, the level of gene expression is measured by reference to genes which encode a protein product and, more particularly, said level of expression is measured at the protein level.

[0605] In another particularly preferred embodiment, said gene expression is assessed by the association of DNA with chromatin proteins carrying repressive modifications, for example, methylation of lysines 9 or 27 of histone H3.

[0606] The present invention should be understood to encompass methods of detection based on identifying both proteins and/or nucleic acid molecules in one or more biological samples. This may be of particular significance to the extent that some of the neoplastic markers of interest may correspond to genes or gene fragments which do not encode a protein product. Accordingly, to the extent that this occurs it would not be possible to test for a protein and the subject marker would have to be assessed on the basis of transcription expression profiles or changes to genomic DNA.

[0607] The term "protein" should be understood to encompass peptides, polypeptides and proteins (including protein fragments). The protein may be glycosylated or unglycosylated and/or may contain a range of other molecules fused, linked, bound or otherwise associated to the protein such as amino acids, lipids, carbohydrates or other peptides, polypeptides or proteins. Reference herein to a "protein" includes a protein comprising a sequence of amino acids as well as a protein associated with other molecules such as amino acids, lipids, carbohydrates or other peptides, polypeptides or proteins.

[0608] The proteins encoded by the neoplastic markers of the present invention may be in multimeric form meaning that two or more molecules are associated together. Where the same protein molecules are associated together, the complex is a homomultimer. An example of a homomultimer is a homodimer. Where at least one marker protein is associated with at least one non-marker protein, then the complex is a heteromultimer such as a heterodimer.

[0609] Reference to a "fragment" should be understood as a reference to a portion of the subject nucleic acid molecule or protein. This is particularly relevant with respect to screening for modulated RNA levels in stool samples since the subject RNA is likely to have been degraded or otherwise fragmented due to the environment of the gut. One may therefore actually be detecting fragments of the subject RNA molecule, which fragments are identified by virtue of the use of a suitably specific probe.

[0610] Although the preferred method is to detect the expression product or DNA changes of the neoplastic markers for the purpose of diagnosing neoplasia development or predisposition thereto, the detection of converse changes in the levels of said markers may be desired under certain circumstances, for example, to monitor the effectiveness of therapeutic or prophylactic treatment directed to modulating a neoplastic condition, such as adenoma or adenocarcinoma development. For example, where reduced expression of the subject markers indicates that an individual has developed a condition characterized by adenoma or adenocarcinoma development, for example, screening for an increase in the levels of these markers subsequently to the onset of a therapeutic regime may be utilized to indicate reversal or other form of improvement of the subject individual's condition. The method of the present invention is therefore useful as a one off test or as an on-going monitor of those individuals thought to be at risk of neoplasia development or as a monitor of the effectiveness of therapeutic or prophylactic treatment regimens directed to inhibiting or otherwise slowing neoplasia development.

[0611] Means of assessing the subject expressed neoplasm markers in a biological sample can be achieved by any suitable method, which would be well known to the person of skill in the art. To this end, it would be appreciated that to the extent that one is examining either a homogeneous cellular population (such as a tumor biopsy or a cellular population which has been enriched from a heterogeneous starting population) or a tissue section, one may utilize a wide range of techniques such as in situ hybridization, assessment of expression profiles by microassays, immunoassays and the like (hereinafter described in more detail) to detect the absence of or downregulation of the level of expression of one or more markers of interest. However, to the extent that one is screening a heterogenous cellular population or a bodily fluid in which heterogeneous populations of cells are found, such as a blood sample, the absence of or reduction in level of expression of a particular marker may be undetectable due to the inherent expression of the marker by non-neoplastic cells which are present in the sample. That is, a decrease in the level of expression of a subgroup of cells may not be detectable. In this situation, a more appropriate mechanism of detecting a reduction in a neoplastic subpopulation of the expression levels of one or more markers of the present invention is via indirect means, such as the detection of epigenetic changes.

[0612] Methods of detecting changes to gene expression levels (in addition to the methylation analyses hereinbefore described in detail), particularly where the subject biological sample is not contaminated with high numbers of non-neoplastic cells, include but are not limited to:

[0613] In vivo detection.

[0614] Molecular Imaging may be used following administration of imaging probes or reagents capable of disclosing altered expression of the markers in the intestinal tissues.

[0615] Molecular imaging (Moore et al., BBA, 1402:239-249, 1988; Weissleder et al., Nature Medicine 6:351-355, 2000) is the in vivo imaging of molecular expression that correlates with the macro-features currently visualized using "classical" diagnostic imaging techniques such as X-Ray, computed tomography (CT), MRI, Positron Emission Tomography (PET) or endoscopy.

[0616] Detection of downregulation of RNA expression in the cells by Fluorescent In Situ Hybridization (FISH), or in extracts from the cells by technologies such as Quantitative Reverse Transcriptase Polymerase Chain Reaction (QRTPCR) or Flow cytometric qualification of competitive RT-PCR products (Wedemeyer et al., Clinical Chemistry 48:9 1398-1405, 2002).

[0617] Assessment of expression profiles of RNA, for example by array technologies (Alon et al., Proc. Natl. Acad. Sci. USA: 96:6745-6750, June 1999).

[0618] A "microarray" is a linear or multi-dimensional array of preferably discrete regions, each having a defined area, formed on the surface of a solid support. The density of the discrete regions on a microarray is determined by the total numbers of target polynucleotides to be detected on the surface of a single solid phase support. As used herein, a DNA microarray is an array of oligonucleotide probes placed onto a chip or other surfaces used to amplify or clone target polynucleotides. Since the position of each particular group of probes in the array is known, the identities of the target polynucleotides can be determined based on their binding to a particular position in the microarray.

[0619] DNA microarray technology make it possible to conduct a large-scale assay of a plurality of target nucleic acid molecules on a single solid phase support. U.S. Pat. No. 5,837,832 (Chee et al.) and related patent applications describe immobilizing an array of oligonucleotide probes for hybridization and detection of specific nucleic acid sequences in a sample. Target polynucleotides of interest isolated from a tissue of interest are hybridized to the DNA chip and the specific sequences detected based on the target polynucleotides' preference and degree of hybridization at discrete probe locations. One important use of arrays is in the analysis of differential gene expression, where the profile of expression of genes in different cells or tissues, often a tissue of interest and a control tissue, is compared and any differences in gene expression among the respective tissues are identified. Such information is useful for the identification of the types of genes expressed in a particular tissue type and diagnosis of conditions based on the expression profile.

[0620] Measurement of altered neoplastic marker protein levels in cell extracts, for example by immunoassay.

[0621] Testing for proteinaceous neoplastic marker expression product in a biological sample can be performed by any one of a number of suitable methods which are well known to those skilled in the art. Examples of suitable methods include, but are not limited to, antibody screening of tissue sections, biopsy specimens or bodily fluid samples. To the extent that antibody-based methods of diagnosis are used, the presence of the marker protein may be determined in a number of ways such as by Western blotting, ELISA or flow cytometry procedures. These, of course, include both single-site and two-site or "sandwich" assays of the non-competitive types, as well as in the traditional competitive binding assays. These assays also include direct binding of a labeled antibody to a target.

[0622] Determining altered expression of protein neoplastic markers on the cell surface, for example by immunohistochemistry.

[0623] Determining altered protein expression based on any suitable functional test, enzymatic test or immunological test in addition to those detailed in points (iv) and (v) above.

[0624] A person of ordinary skill in the art could determine, as a matter of routine procedure, the appropriateness of applying a given method to a particular type of biological sample.

[0625] A related aspect of the present invention provides a molecular array, which array comprises a plurality of:

[0626] (i) nucleic acid molecules comprising a nucleotide sequence corresponding to any two or more of the neoplastic marker DNA hereinbefore described or a sequence exhibiting at least 80% identity thereto or a functional derivative, fragment, variant or homologue of said nucleic acid molecule; or

[0627] (ii) nucleic acid molecules comprising a nucleotide sequence capable of hybridizing to any one or more of the sequences of (i) under medium stringency conditions or a functional derivative, fragment, variant or homologue of said nucleic acid molecules; or

[0628] (iii) nucleic acid probes or oligonucleotides comprising a nucleotide sequence capable of hybridizing to any two or more of the sequences of (i) under medium stringency conditions or a functional derivative, fragment, variant or homologue of said nucleic acid molecule; or

[0629] (iv) probes capable of binding to any two or more of the proteins encoded by the nucleic acid molecules of (i) or a derivative, fragment or, homologue thereof wherein the level of expression of said marker genes of (i)-(iii) or proteins of (iv) is indicative of the neoplastic state of a cell or cellular subpopulation derived from the large intestine.

[0630] Preferably, said percent identity is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%.

[0631] "Hybridization" refers to the process by which a nucleic acid strand joins with a complementary strand through base pairing. Hybridization reactions can be sensitive and selective so that a particular sequence of interest can be identified even in samples in which it is present at low concentrations. Stringent conditions can be defined by, for example, the concentrations of salt or formamide in the prehybridization and hybridization solutions, or by the hybridization temperature, and are well known in the art. For example, stringency can be increased by reducing the concentration of salt, increasing the concentration of formamide, or raising the hybridization temperature, altering the time of hybridization, as described in detail, below. In alternative aspects, nucleic acids of the invention are defined by their ability to hybridize under various stringency conditions (e.g., high, medium, and low), as set forth herein.

[0632] Reference herein to a low stringency includes and encompasses from at least about 0 to at least about 15% v/v formamide and from at least about 1 M to at least about 2 M salt for hybridization, and at least about 1 M to at least about 2 M salt for washing conditions. Generally, low stringency is at from about 25-30.degree. C. to about 42.degree. C. The temperature may be altered and higher temperatures used to replace formamide and/or to give alternative stringency conditions. Alternative stringency conditions may be applied where necessary, such as medium stringency, which includes and encompasses from at least about 16% v/v to at least about 30% v/v formamide and from at least about 0.5 M to at least about 0.9 M salt for hybridization, and at least about 0.5 M to at least about 0.9 M salt for washing conditions, or high stringency, which includes and encompasses from at least about 31% v/v to at least about 50% v/v formamide and from at least about 0.01 M to at least about 0.15 M salt for hybridization, and at least about 0.01 M to at least about 0.15 M salt for washing conditions. In general, washing is carried out T.sub.m=69.3+0.41 (G+C) % (Marmur and Doty, J. Mol. Biol. 5:109, 1962). However, the T.sub.m of a duplex DNA decreases by 1.degree. C. with every increase of 1% in the number of mismatch base pairs (Bonner and Laskey, Eur. J. Biochem. 46:83, 1974). Formamide is optional in these hybridization conditions. Accordingly, particularly preferred levels of stringency are defined as follows: low stringency is 6.times.SSC buffer, 0.1% w/v SDS at 25-42.degree. C.; a moderate stringency is 2.times.SSC buffer, 0.1% w/v SDS at a temperature in the range 20.degree. C. to 65.degree. C.; high stringency is 0.1.times.SSC buffer, 0.1% w/v SDS at a temperature of at least 65.degree. C.

[0633] Where nucleic acids of the invention are defined by their ability to hybridize under high stringency, these conditions comprise about 50% formamide at about 37.degree. C. to 42.degree. C. In one aspect, nucleic acids of the invention are defined by their ability to hybridize under reduced stringency comprising conditions in about 35% to 25% formamide at about 30.degree. C. to 35.degree. C. Alternatively, nucleic acids of the invention are defined by their ability to hybridize under high stringency comprising conditions at 42.degree. C. in 50% formamide, 5.times.SSPE, 0.3% SDS, and a repetitive sequence blocking nucleic acid, such as cot-1 or salmon sperm DNA (e.g., 200 n/ml sheared and denatured salmon sperm DNA). In one aspect, nucleic acids of the invention are defined by their ability to hybridize under reduced stringency conditions comprising 35% formamide at a reduced temperature of 35.degree. C.

[0634] Preferably, the subject probes are designed to bind to the nucleic acid or protein to which they are directed with a level of specificity which minimizes the incidence of non-specific reactivity. However, it would be appreciated that it may not be possible to eliminate all potential cross-reactivity or non-specific reactivity, this being an inherent limitation of any probe-based system.

[0635] In terms of the probes which are used to detect the subject proteins, they may take any suitable form including antibodies and aptamers.

[0636] A library or array of nucleic acid or protein probes provides rich and highly valuable information. Further, two or more arrays or profiles (information obtained from use of an array) of such sequences are useful tools for comparing a test set of results with a reference, such as another sample or stored calibrator. In using an array, individual probes typically are immobilized at separate locations and allowed to react for binding reactions. Primers associated with assembled sets of markers are useful for either preparing libraries of sequences or directly detecting markers from other biological samples.

[0637] A library (or array, when referring to physically separated nucleic acids corresponding to at least some sequences in a library) of gene markers exhibits highly desirable properties. These properties are associated with specific conditions, and may be characterized as regulatory profiles. A profile, as termed here refers to a set of members that provides diagnostic information of the tissue from which the markers were originally derived. A profile in many instances comprises a series of spots on an array made from deposited sequences.

[0638] A characteristic patient profile is generally prepared by use of an array. An array profile may be compared with one or more other array profiles or other reference profiles. The comparative results can provide rich information pertaining to disease states, developmental state, receptiveness to therapy and other information about the patient.

[0639] Another aspect of the present invention provides a diagnostic kit for assaying biological samples comprising one or more agents for detecting one or more neoplastic markers and reagents useful for facilitating the detection by said agents. Further means may also be included, for example, to receive a biological sample. The agent may be any suitable detecting molecule.

[0640] The present invention is further described by reference to the following non-limiting examples.

EXAMPLE 1

CAHM: Colorectal Adenocarcinoma HyperMethylated

[0641] Single-plex performance:

[0642] 74 normals: 0.8 pg hypermethylated/mL plasma (95% CI: 0.2; 1.4)

[0643] 73 adenomas: 9.1 pg hypermethylated/mL plasma (95% CI: -8; 27)

[0644] 73 cancers: 1788 pg hypermethylated/mL plasma (95% CI: 231; 3344).

[0645] The CAHM assay (threshold cut of 3 pg/mL plasma) is 55% sensitive for colorectal cancer with a 93% specificity (FIG. 1).

GRASP: General Receptor for Phosphoinositides 1-Associated Scaffold Protein.

[0646] Single plex performance:

[0647] 34 normals: 1.3 pg hypermethylated/mL plasma (95% CI: 0.2; 2.5)

[0648] 33 adenomas: 0.1 pg hypermethylated/mL plasma (95% CI: -0.1; 0.4)

[0649] 33 cancers: 670.8 pg hypermethylated/mL plasma (95% CI: -470.7; 1812)

[0650] The GRASP assay is 58% sensitive for colorectal cancer with a 100% specificity using a threshold cut of 20 pg methylated/mL plasma (FIG. 2).

IRF4: Interferon Regulatory Factor 4

[0651] Single plex performance:

[0652] 24 normals: 6 pg hypermethylated/mL plasma (95% CI: 2.9; 9.0)

[0653] 23 adenomas: 3.7 pg hypermethylated/mL plasma (95% CI: -0.4; 8.0)

[0654] 33 cancers: 5340 pg hypermethylated/mL plasma (95% CI: -5369; 16049)

[0655] The IRF4 assay is 57% sensitive for colorectal cancer with a 96% specificity using a threshold cut of 20 pg methylated/mL plasma (FIG. 3).

BCAT1: Branched Chain Amino Acid Transaminase 1, Cytosolic

[0656] Single plex performance summary

[0657] 14 normals: 0 pg hypermethylated/mL plasma (95% CI: na)

[0658] 13 adenomas: 0.4 pg hypermethylated/mL plasma (95% CI: -0.4; 1.3)

[0659] 13 cancers: 4088 pg hypermethylated/mL plasma (95% CI: -4459; 10539)

[0660] The BCAT1 assay is 62% sensitive for colorectal cancer with a 100% specificity using a threshold cut of 3 pg methylated/mL plasma (FIG. 4).

IKZF1: IKAROS Family Zinc Finger 1

[0661] Single plex performance summary

[0662] 14 normals: 0 pg hypermethylated/mL plasma (95% CI: na)

[0663] 13 adenomas: 0 pg hypermethylated/mL plasma (95% CI: na)

[0664] 13 cancers: 113 pg hypermethylated/mL plasma (95% CI: -43; 270)

[0665] The IKZF1 assay is 54% sensitive for colorectal cancer with a 100% specificity using a threshold cut of 3 pg methylated/mL plasma (FIG. 4).

[0666] The methylation levels of the five genes were measured in the same 14 normals, 13 adenomas and 13 cancers. The table below demonstrates the improvement in clinical utility when measuring the methylation in TWO of the genes:

TABLE-US-00009 (% sens; % spec) CAHM>.sub.6 pg/mL GRASP.sub.>20 pg/mL IRF4.sub.>20 pg/mL BCAT.sub.>3 pg/mL IKZF1.sub.>3 pg/mL CAHM>.sub.6 pg/mL 54%; 100% 62%; 100% 69%; 100% 69%; 100% 69%; 100% GRASP.sub.>20 .sub.pg/mL -- 54%; 100% 69%; 100% 77%; 100% 77%; 100% IRF4.sub.>20 .sub.pg/mL -- -- 54%; 100% 85%; 100% 69%; 100% BCAT.sub.>3 .sub.pg/mL -- -- -- 62%; 100% 77%; 100% IKZF1.sub.>3 .sub.pg/mL -- -- -- -- 54%; 100%

[0667] Combining the methylation levels measured in any three of the five genes resulted in:

[0668] CAHM.sub.6 pg/mL-GRASP.sub.20 pg/mL-IRF4.sub.20 pg/mL: 77% sensitivity and 100% specificity

[0669] CAHM.sub.6 pg/mL-GRASP.sub.20 pg/mL-BCAT.sub.3 pg/mL: 77% sensitivity and 100% specificity

[0670] CAHM.sub.6 pg/mL-GRASP.sub.20 pg/mL-IKZF1.sub.3 pg/mL: 77% sensitivity and 100% specificity

[0671] CAHM.sub.6 pg/mL-IKZF1.sub.3 pg/mL-BCAT.sub.3 pg/mL: 77% sensitivity and 100% specificity

[0672] GRASP.sub.20 pg/mL-IKZF1.sub.3 pg/mL-BCAT.sub.3 pg/mL: 85% sensitivity and 100% specificity

[0673] Combining the methylation levels from all five genes results in a 92% sensitivity and 100% specificity:

[0674] Targeted Amplicon Sequences for GRASP, CAHM, IRF4, IKZF1 and BCAT1

[0675] The wild-type DNA sequence of the CAHM MSP amplicon is located on Chromosome 6, plus strand; 163,834,393163,834,455 (Hg19) GAAGGAAGCA TTTCGAGCAC GACTGACGCT CCCCTTATTA TTTGCTAAGC CGCTGCGCTC GGG

[0676] The wild-type DNA sequence of the GRASP MSP amplicon is located on Chromosome 12, plus strand; 52,400,88652,400,973 (Hg19) cggaagtcgc gcccgccgct ccggtcccga ccccgggacc ccctgccgca gccgccaccc ctgggccccc agcggacgag ctgtacgc

[0677] The wild-type DNA sequence of the IKZF1 MSP amplicon is located on Chromosome 7, plus strand; 50,343,86750,343,961 (Hg19) gacgacgcac cctctccgtg tcccgctctg cgcccttctg cgcgccccgc tccctgtacc ggagcagcga tccgggaggc ggccgagagg tg

[0678] The wild-type DNA sequence of the BCAT1 MSP amplicon is located on Chromosome 12, minus strand; 25,101,99225,102,093 (Hg19) gtcttcctgc tgatgcaatc CGctaggtcg cgagtctccg ccgcgagagg gccggtctgc aatccagccc gccacgtgta ctcgccgccg cctcg

[0679] The wild-type DNA sequence of the IRF4 MSP amplicon is located on Chromosome 6, minus strand; 392,036392,145 (Hg19) tgggtgcctt ggacggcccc gcctcagcca ctcctggggc cccgacagtc cggttagctc atcccgtcca gcttgtggcg accccgtcgc aggagcgcgg agggcaggcg

[0680] PCR Protocols Used to Measure the Methylation Levels Across GRASP, CAHM, IRF4, IKZF1 and BCAT1 in Plasma Specimens

Real-Time PCR Protocols GRASP, CAHM, IRF4, BCAT1, IKZF1

TABLE-US-00010

[0681] Real-time PCR protocols GRASP, CAHM, IRF4, BCAT1, IKZF1 CAHM GRASP IRF4 BCAT1 IKZF1 FWD 5`GAAGGA 5`CGGAAG 5`TGGGTG 5`GTTTTTTT 5`GACGACGT Primer AGTATTT TCGCGTTC TTTTGGA GTTGATGT ATTTTTTTCG CGAGTAC GTC CGGTTTC AATTCGTT TGTTTC GATTGAC 200 nM 400 nM AGGTC 200 nM 200 nM final final 200 nM final final final REV 5`CCCGAA 5`GCGTACA 5`CGCCTA 5`CAATACC 5`GCGCACCT primer CGCAACG ACTCGTCC CCCTCCG CGAAACGA CTCGACCG ACTTAA GCTAA CG CGACG 200 nM 200 nM 200 nM 400 nM 200 nM final final final final final Probe na [HEX] [HEX] [HEX] na TTCGATTT TCGTTTA TTCGTCGC CGGGATTT GTTTGTG GAGAGGGT TTTGTCGT GCGATTT CGGTT AGTC CGTCG [BHQ] [BHQ1] [BHQ1] 200 nM 100 nM 200 nM final final final 1x PCR Platinum Platinum Platinum Platinum GoTaq Hot Taq DNA Taq Taq DNA Taq Start buffer. polymerase DNA polymerase DNA 1x buffer (Invitrogen) polymerase (Invitrogen) polymerase contains (Invitrogen) (Invitrogen) 2 mM MgC12 (Promega) Final 4.0 4.0 3.0 4.0 +1.0 MgCL.sub.2 conc. [Mm] dNTPs 0.2 mM 0.2 mM 0.2 mM 0.2 mM -- SYBR 1/120,000 na na na 1/120,000 LC480 cycling conditions 1x 95.degree. C.; 95.degree. C.; 95.degree. C.; 95.degree. C.; 95.degree. C.; 2 min 2 min 2 min 2 min 2 min 3x 92.degree. C.; 92.degree. C.; 50 cycles: 50 cycles: 50 cycles: 15 sec 15 sec 95.degree. C.; 95.degree. C.; 95.degree. C.; 62.degree. C.; 64.degree. C.; 10 15 sec 15 sec 15 sec 15 sec sec 62.degree. C.; 62.degree.C; 72.degree. C.; 72.degree. C.; 61.degree. C.; 30 sec 30 sec 20 sec 20 sec 20 72.degree. C.; 72.degree. C.; sec 30 sec 30 sec 47x 82.degree. C.; 85.degree. C., (w/quant) (w/quant) (w/quant) 15 sec 15 sec 62.degree. C.; 64.degree. C.; 15 sec 15 sec 72.degree. C.; 72.degree. C.; 20 sec 20 sec (w/quant) (w/quant) melt 95.degree. C.; na na na 95.degree. C.; curve 5 sec 5 sec analysis 65.degree. C.; 65.degree. C.; 1 min 1 min 97.degree. C. 97.degree. C. continuous continuous 0.11 deg/sec 0.11 deg/sec Correct <80.degree. C. na na na 82.9-83.2.degree. C. Melt Temp (.degree. C.)

TABLE-US-00011 TABLE 1 Current Resulting sub- bisulphite Oligonucleotide region(s) converted sequences for of sequence measurement interest Coordinates (strands of Genomic (genomic of sub- no longer methylation Gene Strand sequence) region(s) complementary) levels BCAT1 top 5`- 25,101,992- 5`- strand cagtgccCGaggC 25,102,093 tagtgttCGaggCGgC GgCGgCGagtac GgCGagtataCGtgg aCGtggC CGggttgga Gggctggattgcaga ttgtagatCGgttttttCG cCGgccctctCGC CGgCGgagattCGC GgCGgagactCG GatttagC Ggattgtatta CGacctagCGgatt gtaggaagat gcatcagcaggaaga c (SEQ ID NO. 1) minus 3`- 3`- 5`- strand gtcacggGCtccG gttatggGCtttGCtGC gtttttttgttgatg CcGCcGCtcatgt tGCttatgtGCattGCtt taattcgttaggtc GCaccGCc gatttaatg 5`- cgacctaacgtctgG tttgGCtgggagaGCG caatacccgaaa CcgggagaGCGC CtGCttttgaGCGCtg cgacgacg cGCctctgaGCG gattGCttaatgtagttgtt 5`- CtggatcGCctaac tttttg ttcgtcgcgaga gtagtcgtccttctg gggtcggtt 5`- tttttgttgatgtaa ttcgttaggtc 5`- attacaaaccga ccctctcg top 5`- 25,101,909- This sequence 5`- strand agatcccaagggtC 25,101,995 is for agatcccaaggg GtagcccctggcCG measuring CpG tcgtagc tgtggacCGg methylation 5`- gtctgCGgctgcaga levels actgccccaggt gCGCGctccCGg using cttgct ctgcagcaagacctg methylation gggcagt (SEQ ID sensitive restriction NO. 2) enzymes (e.g. HbaII, HhaI (underlined) minus 3`- strand tctagggttcccaGC atcggggaccgGCa cacctgGCc cagacGCcgacgtc tcGCGCcaggGC cgacgtcgttctggac cccgtca IKZF1 top 5`- 50,343,867- 5`- 5`- strand gaCGaCGcaccct 50,343,961 gaCGaCGtatttttttC gacgacgtattttt ctcCGtgtccCGct GtgtttCGttttgCGtttt ttcgtgtttc ctgCGccctt tttgCGCG 5`- ctgC GCGcccCG tttCGttttttgtatCGga gcgcacctctcg ctccctgtacCGgag gtagCGattCGggagg accg cagCGatcCGgga CGgtCGagaggtgC 5`- ggCGgcCGagag Gt tttgtatcggagta gtgCGc (SEQ ID gcgattcgggag NO. 3) minus 3`- 3`- strand ctGCtGCgtggga ttGCtGCgtgggagag gagGCacaggGC GCataggGCgagatG gagacGCgg Cgggaa gaagacGCGCgg gatGCGCgggGCga gGCgagggacatg gggatatgGCtttgttG GCctcgtcGCtag CtagGCtttttGCtgG GCcctccGCcgG CtttttatGCg CtctccacGCg top 5`- 50,343,804- This sequence 5`- strand cCGgagttgCGgct 50,343,895 is for ggagttgcggct gagaCGCGCGc measuring CpG gagac CGCGCG methylation levels 5`- agcCGgggaactC using methylation agagcgggaca GgCGaCGgggC sensitive cggaga GgggaCGggaCG restriction aCGcaccctctcCG enzymes (e.g. tgtccCGctct HbaII, HhaI (SEQ ID NO. 4) (underlined) minus 3`- strand gGCctcaacGCcg actctGCGCGCg GCGCGC tcgGCcccctgaG CcGCtGCcccGC ccctGCcctGCtG CgtgggagagGCa caggGCgaga IRF4 top 5`- 392,036- 5`- 5`- strand CGcctgccctcCG 392,145 CGtttgtttttCGCGtttt gtttttgcgacgg CGctcctgCGaC tgCGaCGgggtCGtt ggtc GgggtCGcc ataagttg 5`- acaagctggaCGgg gaCGggatgagttaatC taaaaccccgac atgagctaacCGga GgattgtCGgggttttag aatccg ctgtCGgggcccca gagtggttgaggCGgg ggagtggctgaggC gtCGtttaaggtattta GgggcCGtccaag gcaccca (SEQ ID NO. 5) minus 3`- 3`- 5`- strand GCggacgggagG GCggatgggagGCG tgggtgttttgga CGCgaggacGCt CgaggatGCtGCttta cggtttc GCcccaGC GCggtgtttg 5`- ggtgttcgacctGCc atttGCtttatttgattgG tagttatttttggg ctactcgattgGCctg CttgataGCtttggggttt gtttcgatagttc acaGCcccggggtc ttattgattttGCtttgGC 5`- ctcaccgactccGCc aggttttgtgggt cgcctaccctcc ccgGCaggttccgtg gcg ggt 5`- tcgtttagtttgtg gcgatttcgtcg GRASP top 5`- 52,400,821- 5`- 5`- strand caggaagctgcagca 52,401,051 taggaagttgtagtagaag cggaagtcgcgt gaaggaggaggCG gaggaggCGgCGgtt tcgtc gCGgcca atttCGga 5`- cccCGgacccCGc tttCGtCGttCGgatttt gcgtacaactcgt CGccCGgactccC CGattCGgaagtCGC ccgctaa GactCGgaagtCG GttCGtCGtttCGgttt 5`- CGccCGcCGctc CGatttCGggattttttgt ttcgatttcgggat CGgtccCGacccC CGtagtCGttatttttgg tttttgtcgtagtc GggaccccctgcC gtttttagCGgaCGagtt 5`- GcagcCGccaccc gtaCGCGgCGttgga cggattttcgattc ctgggcccccagCG ggattattattttgtC Gagt ggaagt gaCGagctgtaCG tgtatCGCGCGttCG CGgCGctggagga tCGtgttCGggggtattt ctatcaccctgcCGa tgtttCGtCGaaaggtg gctgtacCGCGC CGtttttCGttCGttttta GctCGcCGtgtcC ggatttgtttagttttttttC Gggggcaccctgcc Gattttttatagggtttgttg cCGcCGaaaggtg atttCG CGtccccCGccC Gccttcaggatctgct cagcccctctcCGac tccctacagggcctgc tgactcCG (SEQ ID NO. 6) 3`- minus gtccttcgacgtcgtct strand tcctcctccGCcGC 3`- cggtgggG gttttttgatgttgtttttt CctgggGCgGCg ttttttGCtGCtggtgggGC gGCctgaggGCtg ttgggGC aGCctcaGCGCg gGCggGCttgaggG gGCgGCgagGC CtgaGCtttaGCGCg caggGCtgggGCc gGCgGCgagGCtag ctgggggacgGCgt gGCtgggGCtttgggg 5`- cgGCggtggggacc gatgGCgttgGCggtg ggtagggtgtttt cgggggtcGCctG gggatttgggggttGCtt cggatac CtcgacatGCGCc GCttgatatGCGCtG 5`- GCgacctcctgatag Cgattttttgatagtgggat aacgaacgaact tgggacgGCtcgac gGCttgatatgGCGC atacgcgac atgGCGCGCga GCgaGCgGCatagG GCgGCacagGCc CttttgtgggatgggGC cccgtgggacgggG gGCtttttatGCagggg CgGCtttccacGC GCggGCggaagtttta aggggGCggGCg gatgagttggggagagG gaagtcctagacgagt Ctgagggatgttttggatg cggggagagGCtga attgagGC gggatgtcccggacg actgagGC top 5`- 52,401,407- 5`- strand gacagagacagcccc 52,401,664 gatagagatagttttaggta aggcaagttgaaggtc agttgaaggttCGagagt CGagagc tttCGgtgg cccCGgtgggagaa gagaagCGggtCGgt gCGggcCGgtggc ggttgCGtCGCGtgC tgCGcCGCGtgC Gtttttattttgaggaagtg Gttctcactctgagga CGtggggagtC Gttgat agtgCGtggggagc ttCGgatagtatattttttC CGctgactcCGgat GaggggatttttCGatttt agcacacccttcCGa tgggttgggggtttgtCG ggggactcccCGatt tttggttttaCGtttgaCG cctgggctgggggcc taCGgggCGCGagg tgcCGcctggcccc gttattgttttttg aCGtctgaCGtaC gatttttgt GgggCGCGaggg CGgaatCGgaCGtag ccactgctccctggac tgggaggggtCGtagg ttctgtCGgaacCG gaCGcagtgggagg ggtCGcagg (SEQ ID NO. 7) minus 3`- 3`- 5`- strand ctgtctctgtcggggtc ttgtttttgttggggtttgttt cggagttagcgg cgttcaacttccagG aatttttagGCttttgggg ttttttacg Ctctcgggg GCtattttttt 5`- GCcaccctcttcGC tGCttgGCtattgatGC cgataaaaaaaa ccgGCcaccgacG gGCGCatGCaagagt cgaaccga CgGCGCacGCa gagatttttttatGCatttttt 5`- agagtgagactccttc gGCgattgagGCttatt agagtgagaacg acGCacccctcgG gtgtgggaagGCttttttg tacgcggc CgactgagGCctat agggGCtaaggatttgat cgtgtgggaagGCt ttttggatgGCggattgg cccctgagggGCta ggtGCagattGCatG aggacccgacccccg CtttGCGCttttggtgat gacgGCggaccgg gagggatttgaagataG ggtGC agactGC at CtttgGCttGCgttatttt GCcccGCGCtcc ttttaGCgttt cggtgacgagggacc tgaagacaGCcttg GCctGCgtcaccct ccccaGCgtcc top 5`- This sequence 5`- strand gacagagacagcccc is for caagttgaaggt aggcaagttgaaggtc measuring CpG ccgagagc CGagag methylation 5`- ccccCGgtgggag levels cgcacttcctcag agCGggcCGgtgg using agtgaga ctgCGcCGCGta methylation CGttctcactctgagg sensitive aagtgCGtggggag restriction cCGctaactcCGg enzymes (e.g. atagcacacccttcC HbaII, HhaI GaggggactcccC (underlined) Gattcctgggctggg ggcctgcCGcctgg ccccaCGtctgaCG taCGgggCGCGa gggccactgctccctg gacttctgtCGgaac CGgaCGcagtggg aggggtCGcagg minus 3`- strand ctgtctctgtcggggtc cgttcaacttccagG Ctctcgggg GCcaccctcttcGC ccgGCcaccgacG CgGCGCacGCa agagtgagactccttc

acGCacccctcgG CgactgagGCctat cgtgtgggaagGCt cccctgagggGCta aggacccgacccccg gacgGCggaccgg ggtGCagactGCat GCcccGCGCtcc cggtgacgagggacc tgaagacaGCcttg GCctGCgtcaccct ccccaGCgtcc CAHM top 5`- 163,834,295 5`- 5`- strand atctgtaaaaatgttga 163,834,500 atttgtaaaaatgttgattttt gaaggaagtattt cttctgcttttcagacta gttttttagattaCGCGta cgagtacgattg CGCGcac tagtttttttatt acc 5`- agcctctttatttcctac ttttattgCGgttttattttttt cccgaacgcaac tgCGgcttcattccct aCGgaatattgaCGtta gacttaa caCGgaacactgaC tCGCGaaggaagtattt 5`- GccatCGCGaag CGagtaCGattgaCGt gcctctaaaaaa gaagcatttCGagca tttttttattatttgttaagtC acgatcttattaca CGactgaCGctccc GttgCGttCGggtttgg cc cttattatttgctaagc ttaCGatttgtttttagaat CGctgCGctCGg aaCGggaaggtgtaata gtctggctaCGatttg aga ctttcagaataaCGg gaaggtgcaacaaga (SEQ ID NO. 8) minus 3`- strand ctgtctctgtcggggtc cgttcaacttccagG Ctctcgggg GCcaccctcttcGC ccgGCcaccgacG CgGCGCacGCa agagtgagactccttc acGCacccctcgG CgactgagGCctat cgtgtgggaagGCt cccctgagggGCta aggacccgacccccg gacgGCggaccgg ggtGCagactGCat GCcccGCGCtcc cggtgacgagggacc tgaagacaGCcttg GCctGCgtcaccct ccccaGCgtcc CAHM top 5`- 163,834,295 5`- 5`- strand atctgtaaaaatgttga 163,834,500 atttgtaaaaatgttgattttt gaaggaagtattt cttctgcttttcagacta gttttttagattaCGCGta cgagtacgattg CGCGcac tagtttttttatt acc 5`- agcctctttatttcctac ttttattgCGgttttattttttt cccgaacgcaac tgCGgcttcattccct aCGgaatattgaCGtta gacttaa caCGgaacactgaC tCGCGaaggaagtattt 5`- GccatCGCGaag CGagtaCGattgaCGt gcctctaaaaaa gaagcatttCGagca tttttttattatttgttaagtC acgatcttattaca CGactgaCGctccc GttgCGttCGggtttgg cc cttattatttgctaagc ttaCGatttgtttttagaat CGctgCGctCGg aaCGggaaggtgtaata gtctggctaCGatttg aga ctttcagaataaCGg gaaggtgcaacaaga (SEQ ID NO. 8) minus 3`- 3`- 5`- strand tagacatttttacaactg tagatatttttataattgaag gaaacactaacg aagacgaaaagtctg atgaaaagtttgatGCG ccatcg atGCGCg Cgtgttggag 5`- tgtcggagaaataaag aaataaaggatgatGCtg cgtagttagattc gatgacGCcgaagt aagtaagggagtGCtttg gagcgtag aagggagtGCcttgt tgattGCggtaGCGCt 5`- gactGCggtaGCG ttttttgtaaaGCttgtGC aggggagcgtta CttccttcgtaaaGCt tgattGCgaggggaata gtcgtgttcgaaa cgtGCtgactGCga ataaatgatttgGCgatG ggggaataataaacg CgaGCttagattgatG attcgGCgacGCg CtaaatgaaagttttattG aGCccagaccgatG Cttttttatgttgtttt Ctaaacgaaagtctta ttGCccttccacgttg ttct minus 3`- 163,834,621 tgGCatgatgaaaggttg 5`- strand cgGCacgacgaaag 163,834,906 gagagttgtttagtGCttg gtttttttcggcga gtcggagagtcgttta tgGCtttttttggtGCtG taaagc gtGCttgt CtGCtGCtttttttGCa 5`- gGCtttcttcggtGC GCGCGCatgaaggg cgcctctacgaa cGCcGCtGCcctc aGCtGCtgttttGCtttt actctacg cccGCaGCGCG gGCttGCGCgGCtg 5`- CacgaagggaGCc GCttttGCggGCtGC cgtcggtcgagg GCtgtttcGCcctcg gttttaggGCgtttttGCt gcgttc GCccGCGCgGC tGCgGC GCtgtGC cgGCtcccGCgg GCggaGCtttttggagt GCcGCgtctcagg ttgagaataggaGCtga GCgtctccGCctG gaggGCggggtggag CgGCGCcgtGC GCgggGCgttggttttg GCggaGCttttcgg gGCGCgGCattGCt agtttgagaatagga tggGCtGCtggtttttttt GCcgagaggGCg gggtggttgggagGC gggtggagGCggg tgGCat GCgtcggttctggG CGCgGCaccGC ccggGCtGCcggtt cctttcgggtggtcgg gagGCtgGCac

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Sequence CWU 1

1

931102DNAHomo sapiens 1cagtgcccga ggcggcggcg agtacacgtg gcgggctgga ttgcagaccg gccctctcgc 60ggcggagact cgcgacctag cggattgcat cagcaggaag ac 102287DNAHomo sapiens 2agatcccaag ggtcgtagcc cctggccgtg tggaccgggt ctgcggctgc agagcgcggt 60cccggctgca gcaagacctg gggcagt 87395DNAHomo sapiens 3gacgacgcac cctctccgtg tcccgctctg cgcccttctg cgcgccccgc tccctgtacc 60ggagcagcga tccgggaggc ggccgagagg tgcgc 95492DNAHomo sapiens 4ccggagttgc ggctgagacg cgcgccgcgc gagccggggg actcggcgac ggggcgggga 60cgggacgacg caccctctcc gtgtcccgct ct 925110DNAHomo sapiens 5cgcctgccct ccgcgctcct gcgacggggt cgccacaagc tggacgggat gagctaaccg 60gactgtcggg gccccaggag tggctgaggc ggggccgtcc aaggcaccca 1106299DNAHomo sapiens 6caggaagctg cagcagaagg aggaggcggc ggccaccccg gaccccgccg cccggactcc 60cgactcggaa gtcgcgcccg ccgctccggt cccgaccccg ggaccccctg ccgcagccgc 120cacccctggg cccccagcgg acgagctgta cgcggcgctg gaggactatc accctgccga 180gctgtaccgc gcgctcgccg tgtccggggg caccctgccc cgccgaaagg tgcgtccccc 240gcccgccttc aggatctgct cagcccctct ccgactccct acagggcctg ctgactccg 2997258DNAHomo sapiens 7gacagagaca gccccaggca agttgaaggt ccgagagccc ccggtgggag aagcgggccg 60gtggctgcgc cgcgtgcgtt ctcactctga ggaagtgcgt ggggagccgc tgactccgga 120tagcacaccc ttccgagggg actccccgat tcctgggctg ggggcctgcc gcctggcccc 180acgtctgacg tacggggcgc gagggccact gctccctgga cttctgtcgg aaccggacgc 240agtgggaggg gtcgcagg 2588206DNAHomo sapiens 8atctgtaaaa atgttgactt ctgcttttca gactacgcgc acagcctctt tatttcctac 60tgcggcttca ttccctcacg gaacactgac gccatcgcga aggaagcatt tcgagcacga 120ctgacgctcc ccttattatt tgctaagccg ctgcgctcgg gtctggctac gatttgcttt 180cagaataacg ggaaggtgca acaaga 206963DNAHomo sapiens 9gaaggaagca tttcgagcac gactgacgct ccccttatta tttgctaagc cgctgcgctc 60ggg 631088DNAHomo sapiens 10cggaagtcgc gcccgccgct ccggtcccga ccccgggacc ccctgccgca gccgccaccc 60ctgggccccc agcggacgag ctgtacgc 881192DNAHomo sapiens 11gacgacgcac cctctccgtg tcccgctctg cgcccttctg cgcgccccgc tccctgtacc 60ggagcagcga tccgggaggc ggccgagagg tg 921295DNAHomo sapiens 12gtcttcctgc tgatgcaatc cgctaggtcg cgagtctccg ccgcgagagg gccggtctgc 60aatccagccc gccacgtgta ctcgccgccg cctcg 9513110DNAHomo sapiens 13tgggtgcctt ggacggcccc gcctcagcca ctcctggggc cccgacagtc cggttagctc 60atcccgtcca gcttgtggcg accccgtcgc aggagcgcgg agggcaggcg 1101427DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 14gaaggaagta tttcgagtac gattgac 271517DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 15cggaagtcgc gttcgtc 171620DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 16tgggtgtttt ggacggtttc 201729DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 17gtttttttgt tgatgtaatt cgttaggtc 291824DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 18gacgacgtat ttttttcgtg tttc 241919DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 19cccgaacgca acgacttaa 192020DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 20gcgtacaact cgtccgctaa 202115DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 21cgcctaccct ccgcg 152220DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 22caatacccga aacgacgacg 202316DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 23gcgcacctct cgaccg 162428DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 24ttcgatttcg ggattttttg tcgtagtc 282526DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 25tcgtttagtt tgtggcgatt tcgtcg 262621DNAArtificial SequenceDescription of Artificial Sequence Synthetic probe 26ttcgtcgcga gagggtcggt t 2127102DNAHomo sapiens 27tagtgttcga ggcggcggcg agtatacgtg gcgggttgga ttgtagatcg gttttttcgc 60ggcggagatt cgcgatttag cggattgtat tagtaggaag at 10228102DNAHomo sapiens 28gtcttcctgc tgatgcaatc cgctaggtcg cgagtctccg ccgcgagagg gccggtctgc 60aatccagccc gccacgtgta ctcgccgccg cctcgggcac tg 10229102DNAHomo sapiens 29gtttttttgt tgatgtaatt cgttaggtcg cgagttttcg tcgcgagagg gtcggtttgt 60aatttagttc gttacgtgta ttcgtcgtcg tttcgggtat tg 1023029DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 30gtttttttgt tgatgtaatt cgttaggtc 293120DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 31caatacccga aacgacgacg 203221DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 32ttcgtcgcga gagggtcggt t 213326DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 33tttttgttga tgtaattcgt taggtc 263420DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 34attacaaacc gaccctctcg 203519DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 35agatcccaag ggtcgtagc 193618DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 36actgccccag gtcttgct 183787DNAHomo sapiens 37actgccccag gtcttgctgc agccgggacc gcgctctgca gccgcagacc cggtccacac 60ggccaggggc tacgaccctt gggatct 873895DNAHomo sapiens 38gacgacgtat ttttttcgtg tttcgttttg cgtttttttg cgcgtttcgt tttttgtatc 60ggagtagcga ttcgggaggc ggtcgagagg tgcgt 953924DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 39gacgacgtat ttttttcgtg tttc 244016DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 40gcgcacctct cgaccg 164126DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 41tttgtatcgg agtagcgatt cgggag 264295DNAHomo sapiens 42gcgcacctct cggccgcctc ccggatcgct gctccggtac agggagcggg gcgcgcagaa 60gggcgcagag cgggacacgg agagggtgcg tcgtc 954395DNAHomo sapiens 43gcgtattttt cggtcgtttt tcggatcgtt gtttcggtat agggagcggg gcgcgtagaa 60gggcgtagag cgggatacgg agagggtgcg tcgtt 954417DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 44ggagttgcgg ctgagac 174517DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 45agagcgggac acggaga 174692DNAHomo sapiens 46agagcgggac acggagaggg tgcgtcgtcc cgtccccgcc ccgtcgccga gtcccccggc 60tcgcgcggcg cgcgtctcag ccgcaactcc gg 9247110DNAHomo sapiens 47cgtttgtttt tcgcgttttt gcgacggggt cgttataagt tggacgggat gagttaatcg 60gattgtcggg gttttaggag tggttgaggc ggggtcgttt aaggtattta 1104817DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 48gtttttgcga cggggtc 174918DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 49taaaaccccg acaatccg 1850110DNAHomo sapiens 50tgggtgcctt ggacggcccc gcctcagcca ctcctggggc cccgacagtc cggttagctc 60atcccgtcca gcttgtggcg accccgtcgc aggagcgcgg agggcaggcg 11051110DNAHomo sapiens 51tgggtgtttt ggacggtttc gttttagtta tttttggggt ttcgatagtt cggttagttt 60atttcgttta gtttgtggcg atttcgtcgt aggagcgcgg agggtaggcg 1105220DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 52tgggtgtttt ggacggtttc 205327DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 53tagttatttt tggggtttcg atagttc 275415DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 54cgcctaccct ccgcg 155526DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 55tcgtttagtt tgtggcgatt tcgtcg 2656299DNAHomo sapiens 56taggaagttg tagtagaagg aggaggcggc ggttatttcg gatttcgtcg ttcggatttt 60cgattcggaa gtcgcgttcg tcgtttcggt ttcgatttcg ggattttttg tcgtagtcgt 120tatttttggg tttttagcgg acgagttgta cgcggcgttg gaggattatt attttgtcga 180gttgtatcgc gcgttcgtcg tgttcggggg tattttgttt cgtcgaaagg tgcgtttttc 240gttcgttttt aggatttgtt tagttttttt tcgatttttt atagggtttg ttgatttcg 2995717DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 57cggaagtcgc gttcgtc 175820DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 58gcgtacaact cgtccgctaa 205928DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 59ttcgatttcg ggattttttg tcgtagtc 286020DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 60cggattttcg attcggaagt 2061298DNAHomo sapiens 61cggagtcagc aggccctgta gggagtcgga gaggggctga gcagatcctg aaggcgggcg 60ggggacgcac ctttcggcgg ggcagggtgc ccccggacac ggcgagcgcg cggtacagct 120cggcagggtg atagtcctcc agcgccgcgt acagctcgtc cgctgggggc ccaggggtgg 180cggctgcggc agggggtccc ggggtcggga ccggagcggc gggcgcgact ccgagtcggg 240agtccgggcg gcggggtccg gggtggccgc cgcctcctcc ttctgctgca gcttcctg 29862298DNAHomo sapiens 62cggagttagt aggttttgta gggagtcgga gaggggttga gtagattttg aaggcgggcg 60ggggacgtat ttttcggcgg ggtagggtgt tttcggatac ggcgagcgcg cggtatagtt 120cggtagggtg atagtttttt agcgtcgcgt atagttcgtt cgttgggggt ttaggggtgg 180cggttgcggt agggggtttc ggggtcggga tcggagcggc gggcgcgatt tcgagtcggg 240agttcgggcg gcggggttcg gggtggtcgt cgtttttttt ttttgttgta gttttttg 2986320DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 63ggtagggtgt tttcggatac 206421DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 64aacgaacgaa ctatacgcga c 2165258DNAHomo sapiens 65gatagagata gttttaggta agttgaaggt tcgagagttt tcggtgggag aagcgggtcg 60gtggttgcgt cgcgtgcgtt tttattttga ggaagtgcgt ggggagtcgt tgatttcgga 120tagtatattt tttcgagggg atttttcgat ttttgggttg ggggtttgtc gtttggtttt 180acgtttgacg tacggggcgc gagggttatt gttttttgga tttttgtcgg aatcggacgt 240agtgggaggg gtcgtagg 25866258DNAHomo sapiens 66cctgcgaccc ctcccactgc gtccggttcc gacagaagtc cagggagcag tggccctcgc 60gccccgtacg tcagacgtgg ggccaggcgg caggccccca gcccaggaat cggggagtcc 120cctcggaagg gtgtgctatc cggagtcagc ggctccccac gcacttcctc agagtgagaa 180cgcacgcggc gcagccaccg gcccgcttct cccaccgggg gctctcggac cttcaacttg 240cctggggctg tctctgtc 25867258DNAHomo sapiens 67tttgcgattt tttttattgc gttcggtttc gatagaagtt tagggagtag tggttttcgc 60gtttcgtacg ttagacgtgg ggttaggcgg taggttttta gtttaggaat cggggagttt 120tttcggaagg gtgtgttatt cggagttagc ggttttttac gtattttttt agagtgagaa 180cgtacgcggc gtagttatcg gttcgttttt tttatcgggg gttttcggat ttttaatttg 240tttggggttg tttttgtt 2586821DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 68cggagttagc ggttttttac g 216920DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 69cgataaaaaa aacgaaccga 207020DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 70agagtgagaa cgtacgcggc 2071258DNAHomo sapiens 71gacagagaca gccccaggca agttgaaggt ccgagagccc ccggtgggag aagcgggccg 60gtggctgcgc cgcgtgcgtt ctcactctga ggaagtgcgt ggggagccgc tgactccgga 120tagcacaccc ttccgagggg actccccgat tcctgggctg ggggcctgcc gcctggcccc 180acgtctgacg tacggggcgc gagggccact gctccctgga cttctgtcgg aaccggacgc 240agtgggaggg gtcgcagg 2587220DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 72caagttgaag gtccgagagc 207320DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 73cgcacttcct cagagtgaga 2074258DNAHomo sapiens 74cctgcgaccc ctcccactgc gtccggttcc gacagaagtc cagggagcag tggccctcgc 60gccccgtacg tcagacgtgg ggccaggcgg caggccccca gcccaggaat cggggagtcc 120cctcggaagg gtgtgctatc cggagtcagc ggctccccac gcacttcctc agagtgagaa 180cgcacgcggc gcagccaccg gcccgcttct cccaccgggg gctctcggac cttcaacttg 240cctggggctg tctctgtc 25875206DNAHomo sapiens 75atttgtaaaa atgttgattt ttgtttttta gattacgcgt atagtttttt tattttttat 60tgcggtttta tttttttacg gaatattgac gttatcgcga aggaagtatt tcgagtacga 120ttgacgtttt ttttattatt tgttaagtcg ttgcgttcgg gtttggttac gatttgtttt 180tagaataacg ggaaggtgta ataaga 2067628DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 76gaaggaagta tttcgagtac gattgacc 287719DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 77cccgaacgca acgacttaa 197828DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 78gcctctaaaa aaacgatctt attacacc 2879206DNAHomo sapiens 79tcttgttgca ccttcccgtt attctgaaag caaatcgtag ccagacccga gcgcagcggc 60ttagcaaata ataaggggag cgtcagtcgt gctcgaaatg cttccttcgc gatggcgtca 120gtgttccgtg agggaatgaa gccgcagtag gaaataaaga ggctgtgcgc gtagtctgaa 180aagcagaagt caacattttt acagat 20680206DNAHomo sapiens 80ttttgttgta ttttttcgtt attttgaaag taaatcgtag ttagattcga gcgtagcggt 60ttagtaaata ataaggggag cgttagtcgt gttcgaaatg tttttttcgc gatggcgtta 120gtgtttcgtg agggaatgaa gtcgtagtag gaaataaaga ggttgtgcgc gtagtttgaa 180aagtagaagt taatattttt atagat 2068118DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 81gaaacactaa cgccatcg 188221DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 82cgtagttaga ttcgagcgta g 218325DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 83aggggagcgt tagtcgtgtt cgaaa 2584285DNAHomo sapiens 84cacggtcgga gggctggtgg gctttccttg gccgtcgggc ccgccacggc gcgggtcttg 60gctgcggggc ggaggtgggg cgggagagcc gaggataaga gtttgaggct tttcgaggcg 120cgtgccgcgg cgtccgcctc tgcgggactc tgcgccgggc gccctcggcc ggcgcgcccg 180gctcccgctt tgtcgccgag ggaagcacgc gcgacgcccc tcccgtcgcc gccgtggctt 240ctttcggtgt tcgtgatttg ctgagaggct ggaaagcagc acggc 28585285DNAHomo sapiens 85tacggtcgga gggttggtgg gttttttttg gtcgtcgggt tcgttacggc gcgggttttg 60gttgcggggc ggaggtgggg cgggagagtc gaggataaga gtttgaggtt tttcgaggcg 120cgtgtcgcgg cgttcgtttt tgcgggattt tgcgtcgggc gttttcggtc ggcgcgttcg 180gttttcgttt tgtcgtcgag ggaagtacgc gcgacgtttt tttcgtcgtc gtcgtggttt 240ttttcggtgt tcgtgatttg ttgagaggtt ggaaagtagt acggt 2858620DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 86gtttttttcg gcgataaagc 208720DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 87cgcctctacg aaactctacg 208818DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 88cgtcggtcga gggcgttc 188910924DNAHomo sapiens 89cccacccccc acagatgctg tctgtcagga gcaggcaaca gacggtcctg gggtccatct 60gtgctaatgc ttcacaatag agtcccatgt ttccccactg acaccccctc ggcccctcag 120ctgatggcca cttggtggtg

ccaaggcggg aggtgggagg agggagaaga aggcactaag 180agagctacct cttagctcct ggcagtcctc aatccacccc ggccccccac ccaacaagca 240tcctgccatc tggacttgtg caatcactga ggggcggaaa agcaccctct tccacccaca 300cctcttgtag gggatggggg cctagaggac tgggggtggg gaggagaaca cagagtcaag 360gagactagag aagaagactg agccaggcgc aagaactgag acaggcagga ggcagaaagt 420ctttcctggc ctcgcaggtg gacgtggcca ttgcccctct gtgctcctta tgccacgtgt 480ctaacacagc acatgtgcaa ggtaccactc cctaccaggc caagagcctc tgtaacccca 540gtgcccagcc agtacctggc acacagcagg gcttaaatgt tggacaacat cacagagtgg 600ttagattgca ggctctggaa ccaggctgcc tggctttgaa tctcagctct gccgctgagt 660gacttagggc aaattactta tcttctctgg gcctcagttt cctcatctgt aagggaggat 720aatggtgctt atttcgtagg gttgttatga agaccaagtg agttaatgca tgtatgtaaa 780aggacacaca gaacaaacag tgtgcatagc acatgctaag tgctcaataa atgttaactg 840tgaaggcata acagatttgg gaagactggg ggaggaggga ggggacagac aagggcaccg 900cattgccgcc tctgcttctt ggccgatggg tgttgggaca tggagtcccc agcctgtgct 960gctgacgccc tgtggtggct agccgctctt tagacaccag acgctgcctt ccacttcctc 1020ctctcacttc ttattcgggc accactgacg acagagactt cggctgggcc attcccgcct 1080ctcctaccgc ctggcagcca tggtaacagc ctgggggatg gtccctaaga tggggtcaga 1140gaacggctga gcatggccat ccccccagcc ctgaactccc actcagcctg ggctcatccc 1200aacctcctga gtcaagtcca cagtaagcgt ctgtctcctg ggaaggggga tctgaccccg 1260gcatcaggag ctgaggaaag gtgttgccag cagggatcac tcaagcccct tggaggggac 1320aggccagaac taagcctact gctttcaggg tttccacctc ttcccttctt cctagacgtg 1380cgaacagggg gcagcctctt tcagctcttc tggggcagct gcgtcaaggg aaaatcctgg 1440gccctctccc tccctggggg cttctgcgca gtgagttcag ggagtctcct ccctcctcca 1500tcgggcctcc acccctactc ctgcgcagcc ccgctgccgc tctccctgcc ctggagtctc 1560ctgcagcccc ttggatctcc gtgactctcc ctacctcccc gactccccag gcttcttaca 1620gtgacctctt accgtgcccc actccatgaa tcgccagagc tattcgtccc taaatttcaa 1680accttgcgca atgtcccttc acagacccct ccaggtatca cgcagccccg agccccgagc 1740cccgccccgg gggcctcatc ccgccccttc gcgtccgcgg ctcgttttcc cccactgagc 1800gcccagctcc cgcagtttcc ccggccgtcg agcgccgtgg gcggggctcc agggcggcgg 1860cgcctcgcgg ggagggtcct ccgtgctggg ggcgaggcca cccgaggcag ctccccgccc 1920gcccccaacc ccgccccgct ctcggagcct ataaagggag gcgacccgcg gcccgcccgg 1980ctggcatccc ccagccgccg ccagccccgc cgaggggagc cagcgccgtc tctgaggggc 2040gtccggcgcc ggagccatga ccctccgccg actcaggaag ctgcagcaga aggaggaggc 2100ggcggccacc ccggaccccg ccgcccggac tcccgactcg gaagtcgcgc ccgccgctcc 2160ggtcccgacc ccgggacccc ctgccgcagc cgccacccct gggcccccag cggacgagct 2220gtacgcggcg ctggaggact atcaccctgc cgagctgtac cgcgcgctcg ccgtgtccgg 2280gggcaccctg ccccgccgaa aggtgcgtcc cccgcccgcc ttcaggatct gctcagcccc 2340tctccgactc cctacagggc ctgctgactc cgcagtgccc tctcctcggc gtccgcggag 2400tcccccacct tcttccccgg cccgctgggt gcctcgactc cccgcgttcc ccgctgctgc 2460gaaggccgtg gccctcgcct gcacaccgcg cccaggctcg gtggctctta actccgcgcc 2520ccatgcacgc cccctctctc cctccttgac tcctcccagc accccccttc tcctacccgc 2580tccatctggc tttctgcccc ccatgccccg cctccccgtg gccaggtgtc ctgggtcccc 2640aggagcccct cgcccgaggg acagagacag ccccaggcaa gttgaaggtc cgagagcccc 2700cggtgggaga agcgggccgg tggctgcgcc gcgtgcgttc tcactctgag gaagtgcgtg 2760gggagccgct gactccggat agcacaccct tccgagggga ctccccgatt cctgggctgg 2820gggcctgccg cctggcccca cgtctgacgt acggggcgcg agggccactg ctccctggac 2880ttctgtcgga accggacgca gtgggagggg tcgcagggcg cccgcggggc aggaaggatg 2940cgggccgcgc ccacctctga gtcccctctg ccagcctctt cctctggccc caggagacct 3000gaggctcaga acctacacaa caccaggtta agaagagggg cctggtggcc tttcctcacc 3060cagccgccct ccttcgcccc ggcccccagc tagcccccac acaatgaaca gcttgttgag 3120aatttgcatt ttatgaaaat catgttgaaa gacaaagggg tctctctgtg ctgcccagtc 3180cttcctccct ggccgtttgg gaactgtccc cacccctgag gccaatctgg ttctgaacct 3240tctcttcctt gccttgggca gctttggggg agggttagca aaggcacaga acagaaaggc 3300cctgggctgt gcaggctcca aagaaaaggg ctgctctggg actggacctc ctcccaggac 3360caaaaagtta gggagggtga gagactactt tagtttatca aggaccctga agagacagga 3420accttcatct ctcatccttc ctccacaccc cccaccacca cccctaaaga actcccagtc 3480tcggtccttt agtgagactt gctgacaagt ttgacatcta agatgttttg tcccagaaag 3540cacaaaatat atggcaatgg agagagagac ccaggtatag ctgggcacag ctggtcacct 3600gcagctggga tccacaactg gtccttgaaa cggcctgtac cttaggagac ctggcacctc 3660tgaccccaca ttctggctgg gattgccagc ccttcgggac agggtccctg accccagccc 3720tcccaagcca ctgtctgtag ctgagaaatt agatggagag acccaactgg cagaaggtcc 3780tcggagcacc ttgataggtg agcccagggg acacctatcc tctgaatccc actggggaag 3840agcccctgcc tcagctttgg gagtctggat ggcctgagcc tctacagaca tgggccctag 3900gggtggagac cattttagaa taatgatctc cccacctgct gccagtgtgg aaaccagcaa 3960gggcttagag gttcatggat ctggaaccca ggaggatggt tgtgtccctg cagtcccagg 4020tatgaaggta aggcctgtag agaaagttga ggagtggtgc cagtagtggc acttggcaaa 4080tagttccacc agcaccaaaa caggtgtgga tgtggagctg ggaaggggca gacaggaagt 4140gggtcgctgt gtccagggta acctctcagt gtctgctcaa ggacagtccc gccttacctg 4200ctccttctga ccatcttact gcccagggct caggattccg ctggaagaat ctcagccaga 4260gtcctgaaca gcagcggtga gtcaccaaca cccagcccct gccatggtcc aaaggggtga 4320ggtgctgggt tggggggtgc caggacagca tctcagccta gcgagggtag tcattctcct 4380agcctttaaa catggctccc ccgctgggag tgagggcagg tgggggtgag ggctgtgtga 4440agggggtggc agagaaagga ggtagggact tttgagtcat taggtgctct tcaacacacc 4500cccagtccct gccagttacc cctccctggg gagatctgga tgaacggatg tgggagttgg 4560gagggggtgt aggcaaagtc tatggggaac gtcctaaccc aggcctcctg ggctcccctg 4620agccctccta gccttggcaa accccacggg cccagacctt agccaggctg tgtccagctg 4680cttggggctg gctgcccctg cctccagaat gtcagtcctc ttctggtccc agcctgtggc 4740agccctctta ggagggatct gagcgtgggc agaagtaggt gctgactcca ggccctggga 4800ccccacagtt tcccttctct actcatgtcc catccctgat ttgggcttga ctttctctaa 4860aatggatcag caaactgacc tgctagccag attggcctgt ttggcccttg agctaataat 4920ttttaaagag ttgtaaaaat aaaaacaaat aacaatatat gacagagatc ataaggggcc 4980tgcaaagaaa gcctaaagta tttaccattt ggccctttgc agaaaaagtt tgctgaccct 5040tccaaaaaac cctagaacat tggggtagac gcggaactcc cagccaccct gctccctgcc 5100ccaatagtac agagagggga aaggcctgct gttcagagtg agaggggctc gagctggagt 5160ggggaggtgc tgctcagcat ttgggggaat ctctgggtca ggctggaagc ggagaagcct 5220ggtctccagg gcctttccga ggctgagcta cttgaagggg cctttggagg ctgctttaac 5280tgtgcctctg gctgggcggg aaggaagggg gtgggagtgg gcagaggaaa ctctgggctc 5340ccccagcagg cgaggatctg gagcagctcc agaccattgt gtccagcggg caggccttca 5400gtgcgggaag gggcggcctc gaggctcccc tcccccagcc cccacatctg gtgggctggc 5460cccagcatag ctgggaggag cagctgtggt cttgctgagc ctcgtgactg gcctctgggg 5520gtggggccag tcctctctcc aaagctgtgg aacagaggag gctccaggct gtggctgaat 5580ttcgggcctt agctagtcag taagtggtac tgtagggctc actggaaagc tgggatgggg 5640ctaaaaaact cagccggctc atccttcagg ggaccggccc ttctctgtgc ttccctccca 5700ccactagagg ctggattggt tctctgtggc tccatgaggc tgatttcaat tgggtatggg 5760aaagacattc caataatctg tgatgagact gagctgtcac tggagacaga gtcctgctgg 5820aatgttctag accagttgcc aatatccagg gaggcccaag ctatgggact tctacacctt 5880ttaatcctaa ttgtcttgac ccctgtgtct cttgcaggaa agtgctgacg ttggagaagg 5940aggataacca gaccttcggc tttgagatcc aggtgggaga agctgcacac aggggtcagg 6000ggggttggat gaccagcctg agggatgaac ggacttgtcc caaccctggg ctgagggtcc 6060ccttgtccat tacagactta tggccttcac caccgggagg agcagcgtgt ggaaatggtg 6120acctttgtct gccgagttca tgagtctagc cctgcccagc tggctgggct cacaccaggt 6180ggggcctgag cccaggacac ccaggtctgg gaaggggata tgaccttact cccaagcaaa 6240gggggtgagc aatctctcct gaaatcaatt cctcttcctt ttccttcttt gagaaggcca 6300gaaagaagaa tggatagaat ctgggctttg gatctaggca aatttgccat gtactgtgtg 6360atcttgcaca gccccatcta caaaatgagg gtaataatgc atccaaacat cacagtgcgg 6420caaggggatt ccctgggcac actgccaggg cctaattaat ggtggatgat gctgctgctg 6480ctctgattcc tcccagcaac cctggcagtc agcatgggca ggagccaggg aagaagcaac 6540attccattaa gtctgtttga tattggggat caggccaatc ctgccccaaa atgggcccag 6600tgctgaggaa ccgatgttac tcccttttaa aaaattagaa actttttttt tttttaagag 6660acagggcctc agtctgtcac ccaggctaga gtgcagtggc gtaatcataa ctcactataa 6720ccttgaactc ctgggctcaa gcgatcctcc tcttgcctct gcctcccaaa gcaatatgtt 6780acttcctcta acaaggaaat tatgcttcag caggagatcc ctggattgag cagatctaga 6840gtccccaggt tccaggaagg gcagcctgaa actgtatgaa tcaatccccc ctccaccatc 6900tttgccccta agcccctacc tccttcccac ttaccagcag cccgtgctag ctatcttagt 6960ccattttctg ttaccataac agaatacctg atactgggta attataaaga aaagaggttt 7020atttagctca tggttctgga ggctgggaag ttcaagactg ggtggccgca tcaggtgagg 7080gcctcatgct gcgttctgac atgatggatg gcatctcatg gcaggaacgc ctgcaagagt 7140ggtgagtagg cacacgcaaa agagacaaaa catgggtgat cttgctttat agcaacccac 7200tcgccaggta actaaaccag tcctaccaga gcaagaactc actccccaaa aacagcatgg 7260atcccttcac tgggcagatc cttcatggcc caaatgccac tttttttgag atggagtttc 7320gctcttgttg cccaggctgg agtgcaatgg catgatctca gctcactgca gcctctgcct 7380cccagattca agcaattctc ctgcctcagc ctcccgagta gctgggatta caggcactgg 7440ccaccaagcc cagctcattt ttgtattttt agtagagatg gggttttgcc ttgttggcca 7500ggctggtctc gaactcctga cctcaggtga tccacccgcc tcggcctccc aaagtgctgg 7560gattacaggt gtgagccacg gcgctcggcc ccaaatgcct cttaaaggtc ctaccatctc 7620tcagcactgt tacgttgggg atgaagcctc aacatgagtt ttggggacaa acaatattta 7680aatggtagca gtagccaagt ggtatactac aacttctcaa agtagtttca aatccactct 7740ccctccccat catccctgaa gcatccacag cagggatcca tacccctttt tacagatagg 7800aatggggccc tgacatgggg cacactgtgc ttgaggtcag gaagctctcc agtggtgcag 7860ggtagcagaa ctatccctct gggggccagt cattccctgt gcttctctcc caccaccaga 7920ggctggactg attatctgtg gatccatgag gccatgccat gcctggggcc agggtcggtt 7980cccagctggg tgctgctcac ctgctcttcc ctgaattgac tgggtcttat ggccagcgtg 8040gactggacag aaataaccaa atctgagggt agcccagggt cctgggtggg cttagctttg 8100ggacagaact tctttttttt tttttttttt ttgagacgga gtctcgctct gtcgcccagg 8160ctggagtgca gtggcgcgat ctcggctcac tgcaagctcc gcctcccggg ttcacgccat 8220tctcctgcct cagcctcccg agtagctggg actacaggcg cctgctacca cgcccggcta 8280attttttgta tttttagtag agacggggtt tcaccgtgtt agccaggatg gtctcgatct 8340cctgacctcg tgatccgccc gcctcggcct cccaaagtgc tgggattaca ggcgtgagcc 8400accgcgcccg gccggacaga acttcttgag ggcagagtga gggtgttggg tgtgtgaggt 8460ccccaccctt tggctggggt gctgggcgtg gacaacctgg tagtcactac aggcccacaa 8520gaatggctgt ggttctgtgt gtttggatcg agtatgagag atgtcagagg agatctacag 8580agaaccatga ggagttggag gagggagttc aggagtattc cctggagtta ctacccaccc 8640ttctcccctt tctggctaag gtaggaggct ggtattctag catgccccat ggagcaaatc 8700taaccccctt gtctgcctgg caggggacac catcgccagc gtcaatggcc tgaatgtgga 8760aggcatccgg catcgagaga ttgtggacat cattaaggcg tcaggcaatg ttctcaggta 8820tgtctgggag ccgaggtgcc tgaattcctg agctcagcct cttggtattt cctcagcctg 8880tggctcactc aggctttgat tctccaacct cagactggaa actctatatg ggacatcaat 8940tcggaaggca gaactggagg ctcgtctgca gtacctgaag gtaggggaac ctagataacg 9000tccagcctcc accctcctct tcccaagcct ctgccctgtg gggggtcact tacagctgaa 9060tctcctgtaa ctgaagattt cttttgtcta ctccctgatc cctcgtctgt acccacgtcc 9120tgctagtttc ctgctagctt gtgacagtgg ggtggggact gtctcttgca gcaaaccctg 9180tatgagaagt ggggagagta caggtcccta atggtgcagg agcagcggct ggtgcatggt 9240gagtagatcc cggggtgtga ggggccactt gttctgctac agacacccca tctgcgcttc 9300cccctcagaa ctggcgggtt ctagtaaaga acggtttact agtaaacctc cacagtaaag 9360caaggtttgt tgagctacta ctactttggg tactgccgca gccacatttc tggttattct 9420cacactagcc ctctgcaggt aagtaacaga tagtgtcatc ttcactttac agaggggaac 9480accagggctc aaagagtttg tgtcaattat ttccgaggcc cgtttgtgct aagcggcccc 9540cataaggatc tgagtgataa ttcctgattt gcgggtgagg gaagtagggt ctcaggtttg 9600tgcctggcca gggccacaga gatggtcagc aggacggagc ggggacgccc cgcccatgcc 9660ctccgaccct ttgcagaggc caccacggtc caggcctgac ccgcccccta cctctcccgt 9720ctctgcgcag gcctggtggt gaaggacccc agcatctacg acacgctgga gtcggtgcgc 9780tcctgcctct acggcgcggg cctgctcccg ggctcgctgc ccttcgggcc tctgctcgcc 9840gtgcccgggc gtccccgcgg aggcgcccga cgggccaggg gcgacgccga cgacgccgtc 9900taccacacgt gcttcttcgg ggactccgag ccgccggcgc tgccgccccc gccgcccccg 9960gcccgcgcct tcggcccggg ccccgccgag acccctgccg tggggccggg ccctgggccg 10020cgggccgcgc tgagccgcag cgccagtgtg cggtgcgcgg gccctggcgg gggcggaggc 10080gggggcgcgc cgggcgcgct ctggactgag gctcgcgagc aggccctatg cggccccggc 10140ctgcgcaaaa ccaagtaccg cagcttccgc cggcggctgc tcaagttcat ccccggactc 10200aaccgctccc tggaggagga ggagagccag ctgtaggggc gggggcgggc agggaggtat 10260ttatttattt attcgcaaca gccagcgcta aaagaggggg aggccgagcc aagaggaccc 10320caggagccca gagcagcggg agagggtcct tcctagcctc ggcccgccgg gtcggttcct 10380ggctggtgtc tgctgaggga gtggggggcc cagccccttc tcttctcccc cgccaaacca 10440cagtgggagc tggggcaggg ggagagccag gcaatcgggg gccaaagatg ggggtgctcg 10500cctacagtct gcatctgtag tgccttgtgg ggtatccagg aacaccctcc cagcagggga 10560tgggaaccct gtcccatgaa gccctctcct cagctttact tgctcccccg cccttagcct 10620tggggagaaa tggcccgtgg tgggctgacc ccccaccctc cacacacaca gttccatgac 10680ccagcgggcc cccaggggca tcaggtgctg gtcctcctcc ctcctggcct cgacccctaa 10740gggcttcgcc cctcccaggg gcctgtaact aagtcgggtc ctgccaggca gggggcctgt 10800gttctgtgcc ccttgggaga caggaactgg cgagttcagg tggggtgggg acagcacaga 10860ctgttccacc gttgtgcata ttgttgcttc tgaaccacaa actgtataaa tggatggttt 10920tttg 10924902886DNAHomo sapiens 90agcataattt cggtctccta cggaatttct ttaaactaac gagccccaca ctgacttcca 60cttagtattg aacagctgca ccaactcccc aaccacgaaa ccccgcttta gtcctcacgg 120gaggggagag ctcccgaacg cggggcggtg ggggtccgcg cagagcaggc tcgggaggcc 180gagcggagga gcggggcccg cgccgggcac acgcgtcctc caggccggcg gcgcggcgtg 240ggcctgctct cgggagggct cggcgaggac caccgagtcc gcgcagcccc cgccgacctc 300tcggaaatgt gaccgccgaa gctagagggg ccgcagggct caccccgcag ccctccgcaa 360cgcgccaact tggacgccag cggcgcgggg tcccggccgg gcagggggcg tccggcaccg 420gcgggtccac cccggcccgc ccgcccgccg caagcccggc ccggcacctc ctttgtgcgc 480cctcctggcc tcccagtccc cccggcgctc ggtcccgccc ggccgtgacc ttcccgccct 540ccccaccatc ccaagcgggg aaaggggccg ccccggcggg ggtcgggccg gggccggggc 600cctggagacg ctcaccttcg tccagcagcc gctcgaggtg gttgaagatc ccgcagaagt 660tgggcaggct gctcatgagc ttcttgtcgt tcatcagctg catcaggtaa tctggggtgg 720gcttcggctt ctccttcgtt tccatttccc cgaccatatt ccaggctccg cagctcactc 780cgcccgccgc cgccgccgcc gccgccggag aggagggagg ggcgggggcg agccccggcc 840gcgggccgct cgggacccgg cgtcccgctc cgcgccggct cccgctctgg ctcccgcgcc 900gagccccggg gcggccggca ccgcgcgctc gcccgccccc cgcaggcact ttccgcccgg 960gcccgacgcg ctcccagccg ccgccgctct cggccgcccg gctcggcgcg tccctcacga 1020ggccggcggg cgggcgggag gcgggtctcg gctggccgag tgcgggcgcg gggcgcgggc 1080tgctggcgcc ggacgaggag gagccggggc cgccgctcgc tcggctggtc gagcccgctc 1140agcgccgccg ccgcctgtgc cgcgggctcg gggggtctct ctgggctggt ccccgccgcg 1200gcgcctctgc cgctgccgcc gcgctccgac tgcgctcctc ctcttcctcc tcctccttct 1260cctcctcctc ctcctcactc acttggcggc ggagttcgcc tcagttcagg cggcgctgcc 1320agcggcggcg gcagcagcgg cggcggcggg gggaggggca gcggcgcggg gagggccggg 1380ggcgggcggc gggcggggcc gcgcagggcg gccgttagcg ggtcccggcc ggcgcgctcc 1440cgctgcctgc tgcccgccgc cccgcgaccg gggcagccgc cggcgccgcg ccccctcctc 1500cctgcctccc cggcggggcg ggcgacgggg gcaacgggag tgtgacggac tgcggcgctc 1560ggcgggcctg ggcgcaagga ctgggtcgcc gccgtgcggg gcgcccgggg cgggtgggtg 1620tgggctgcgg ggccgacggc cgcggggggg gcgcggggct ttccacggca cggggcgggt 1680ggggctgcgg gcgcggtcgg ggctggcgcg gcaggcgaga ggaattccag cgggacgcgc 1740cagcgctgcc tccgcctcgc ctcccgttac tatagttttt tcagaacctc ttatccaccc 1800cgcagaagag aaattttttt ttaacgtcct gttgcttcac gggggacttt cggggtgggc 1860atcacgtggc ccgacacgta gccgtggggc tccagagcgc gtgcgcgcgt cgagcccggt 1920cgccacgccc cttccgaggg tcgctccgcc cccgtcgggc cccgcgagcg cgcggtgggg 1980gaggggaggg ccccggagcg cgcctgcgtg gggcgggggc ggcagccgac taggggctgg 2040gtctggccgt ttagggccgg gtcttggccc gtcgcccacg gtgcggaggg ctggtgggct 2100ttccttggcc gtcgggcccg ccacggcgcg ggtcttggct gcggggcgga ggtggggcgg 2160gagagccgag gataagagtt tgaggctttt cgaggcgcgt gccgcggcgt ccgcctctgc 2220gggactctgc gccgggcgcc ctcggccggc gcgcccggct cccgctttgt cgccgaggga 2280agcacgcgcg acgcccctcc cgtcgccgcc gtggcttctt tcggtgttcg tgatttgctg 2340agaggctgga aagcagcacg gcggagagga gccttgcact cgccaggcgg gaagcctgcg 2400cggacacgcg tgcgcaccca cggggcggcg ggcgggcgtg gggggtccgg gccacgcggg 2460cgacgcgcct ctagggaagc gatcttgttg caccttcccg ttattctgaa agcaaatcgt 2520agccagaccc gagcgcagcg gcttagcaaa taataagggg agcgtcagtc gtgctcgaaa 2580tgcttccttc gcgatggcgt cagtgttccg tgagggaatg aagccgcagt aggaaataaa 2640gaggctgtgc gcgtagtctg aaaagcagaa gtcaacattt ttacagatga agaaagaata 2700cggaggcaag aggtctttct ctgcagtttg gtggatttcc aacatttaga cttgtttgga 2760agaatttcct cagctgcacc aatgaagtcc ttgatctata gaagtcggca gtccctaaat 2820ctacgtctgc attttgttgc aaatccttta taacattcca ttaaaataat gcagagttat 2880ttaata 28869121705DNAHomo sapiens 91agattagcaa ttacatttaa aaacaaggta gtggtgtgaa ggctcagagt ttcacacaac 60gactgttgtt ctgaactaaa agcagaggat gtggatgagt gaggggaggg tatgttgaaa 120atgactaaac ccggtgcaga ggacacgtat acgaaagtgc aaaaagctct catttgccat 180tttttgtcct cagcaaactc ctctctggta tgtttgtgaa cgtttgaggg aaaggtaaca 240ctgattaaaa tataatgcaa caagaaggca acgatctttg ctttgttcac tgatgtgttc 300caagtgccta ggacggttcc tgacaagtag caggtgctca aaatacattt gtcaagtgaa 360taaatctgtg aaaggaaagg aagaaaaaca ggttgtgacc agaacttttt gtgaacaaaa 420ccctgttgtt tattacatag actttggtaa tggaaaactt acttgggtga aataaaaaat 480ggcatcctgt taatttctga gaacgtctgt tggttttagg aaaagcatac ctatccatac 540ctcactacct gttttgctct agcctaaaca tagattcttc tttggttagg agacattgac 600ccaatatata agattaaaac aaaaactgag aaataagtga aatcaaaagc ttttcaaaag 660ttgcaggttg acctacggtg gtggtggtct aaaatcatat agaaaccaga gatctgatgg 720tttacctgaa aatgcgaagt aaatgcacat actcagcatc tcagacgatc gaaagctcaa 780cgggtgaaag ctcagggggt taattttgcg attaaggaca tcttggaaaa gtatgtaaaa 840tccctggtcc acttaagtat tattcctatt ttgggctttt atttatttat tttgagatgg 900agtcttgctc tgtcgcccac ctcggctcac tgcaacttca gcctcccggg ttcaagcgat 960tctcgtggct cgtcctctca agtagctggg gccacgcccg gctaattttt gtatttttag 1020tagagatggg gtttcaccgt gttggccagg ctggtctcga actcctgacc tcaggcgatc 1080caccgcctcg gcctcccaaa gtgctgggat tacaggcttg agccacagcg cctggcctat 1140tttgggcttt tataccccac tggtaaactg ctttcctcca ggttgaggtt aaaacgacat 1200cattttaagg tgaactgaag tctggaagtg attaagcact

tggatcctta gggagcctct 1260ccccgccccc atctctttca tgctaagata attaaaactt cggggccggg gcattgtctg 1320agtcacttca attcaccagc ctaatagatg caaaaggatg taagcatgtc agacacgcag 1380agacagtatt tgaatcaagc ttaatagctc aagggagctg ggccatttcc tattttcttt 1440ttagtgagtg cgatgttctc taaacaccgc ggagaggcag ggttcccggt gatggccttg 1500ccgagggtgc tcccgcaacc tccacctcca gttctctttg gaccattcct ccgtcttccg 1560ttacacgctc tgcaaagcga agtccccttc gcaccagatt cccgctacta cacgcccccc 1620atttcccgcc ctggccacat cgctgcagtt tagtgattga ctggcctcct gaggtcctgg 1680cgcaaaggcg agattcgcat ttcgcacctc gcccttcgcg ggaaacggcc ccagtgacag 1740tccccgaagc ggcgcgcgcc cggctggagg tgcgctctcc gggcgcggcg cgcggagggt 1800cgccaagggc gcgggaaccc caccccggcc gcggcagccc ccagccttca cgccggccct 1860gaggctcgcc cgcccggccg gccccggctc tcggcttgca aagtccctct ccccagtcca 1920acccccggcc cccacaggcc tcggcgcccc gccccgcccc aggccccgcc ccagagagtt 1980ctataaagtt cctctttccc acctcgcact ctcagtttca ccgctcgatc ttgggaccca 2040ccgctgccct cagctccgag tccagggcga ggtaagggct ggagtcgggc aggaggaggg 2100gtgtgaggct gataccagag aggacccgga gcgcgaacca gaggttcgac ctccagggca 2160gcgcagggta ccccggcttc ggagcgggaa gggagcgcgc cccgtcctgg agctccgact 2220cccaccccat ctgcgctgag ccggaggcgc tggtttgggc tccaaggccc gcctccttgg 2280ctctgcccga gcctccccgc ctgccctccg cgctcctgcg acggggtcgc cacaagctgg 2340acgggatgag ctaaccggac tgtcggggcc ccaggagtgg ctgaggcggg gccgtccaag 2400gcacccacac aagacggcac aactgcctgc gagaaacagg cccggccctg tggaccccaa 2460tccgaggctc cttcccctgc tcttcgttcc taaggggccc aagctcacgg cggcctccgg 2520cgcggtgctc acccgctggc gcaggaggag gaggagctcc acatttgggt cgctccgagc 2580cttgcgtgcg gtggcctagc cggcctggcg cggtccctgc ctcccaggct ccgcagctgt 2640cgtcgccctc tcccgcgccc tccccgcctc cgctctcccg ggcctgctcc ggggtccggc 2700ggacgctctg cgcgcggaat cccccgtact ggggctgcag cccccgcgtc tgcgccactt 2760gtcgtttgca gagcccactt agtgcgcgct agctgggcag ggataggggt cctattcggg 2820gcgaagggtc tggatgcgag cagagaaagc ggagggtgga ggaacccggg gctgcgcccc 2880tggaacgccc ggccgcaggc gaggtcctcc gcgcgtggag gccgccaggg gagtggaaac 2940tgacagagtc gcggggaagg ggcgagaagc gggttgggag tgagcgaagg caagcgagag 3000ctgcgagtga gtgcggaagg agggccagga ggggtggcgg ctgggtgggg agagagggtg 3060caagacgagc ggcgcgtgtc gggagccttt gggctgcggg tgcgttacag gagagcaggc 3120gggtaggagc cttcgcgggg gccgagctcg gaaggcggac ggctgtgccc gcccagggga 3180tgcgcccggg ccggccgcga aggtgccttc ttccgggggc ccggacgacc ctgacacggc 3240acgcgcgcgc ttcgcagcct caaagactcc ggggcctcgt ggtcactggc gcaggggatc 3300ggggcggggt gcccggagtg cggtgcctcg tggctgaagg gcagctcttc tccccgcagt 3360gcagagcaga gcgggcggag gaccccgggc gcgggcgcgg acggcacgcg gggcatgaac 3420ctggagggcg gcggccgagg cggagagttc ggcatgagcg cggtgagctg cggcaacggg 3480aagctccgcc agtggctgat cgaccagatc gacagcggca agtaccccgg gctggtgtgg 3540gagaacgagg agaagagcat cttccgcatc ccctggaagc acgcgggcaa gcaggactac 3600aaccgcgagg aggacgccgc gctcttcaag gtctccggcc tcgggagccg gcgggggcgc 3660gccggggagg gcccagagac agagcccggg gtccccggcg ccgcctccga ggcgagccca 3720ggggaccgcg cggggcggac gggcgggcgg cggaggcatc aggtggcgtc gccggagccg 3780caggaggagg aaaggaggcc tcggctctca gcgggaccgc gggggccggg agccgggtcc 3840tgggcgcgtg gaggctgcag ggaaaccgct gaaggcccgg ccgggcccgg ggaagggcgg 3900ccaaaggctt gaggggtttt gcgcgttcgt ccgtgcgttc tcgtttccac gcaagcctcc 3960cgcccttcct ccgggctccc gtctgccgcc tccgtccgtg ggtccccctc gccctctccg 4020tgcgtccgcg cctgtgccgg cggctgtttt cgtctctcac cgcgtctctg tttctctttt 4080cgctgctttt ctctctgagt ctctctctct ccatgttttt cctgaggtca gcctctcttc 4140tcgctcctgc tagctctctg cgggtactcc cacctctgtc tttctctttg tgtgtctctg 4200tctctctctt tcccccatcg cagtggaact cagggcctct gtctagagct gtctcccttg 4260ccctttgcgc gagtgcacac acgtgtgtcg ttgttacgat tgttctcccc taaggcagtt 4320tacccagaga actacgtgtc tgggcccagc ccccacctgt gggcagagca ggggaagggg 4380acttcctccg ggaatttggt ctcaatttgc tctcagagtg cctcagctgt gctgccatcc 4440agatgtctcc tgtgggtgac agctcacacc acagctgtcc ttagtcctag gcaagctcac 4500tcagacactg ggtgggtaga gccccctcaa ggaacctccg catctcactc taccggttat 4560aaatacccag aaaatgtgtc ttcaacttgg cagtgatagg gtccaagatg gaaaatcatt 4620ttcctagagc atagctgggg tctttcagtt tacgttctga gcaacggtgt aaatctgaag 4680gacctatgcg ccattctttc ttttagaaat acaatttcaa gattccttat aaaatatctg 4740tattttgggt ttagcatggt ggctcacacc tgtaatccca gcactttggg aagatgaggt 4800ggaaggatgc ctatgcaaca tagtgagacc ctgcctctgc aaaaaataat aattaaaaaa 4860attagccagg catggtggtg aacacctgta ggccgagggc ccagctactc tagaggctga 4920gataggagga ccctagaact caggagttcg atgctgcggt gagctatcat cgtgccactg 4980tactctagcc tgggcagcag agcaggactc tgattccaaa aagaaagcta ataaaccaga 5040catgtatttt gacttttcgt tctcttcatt ctttcccacc aggcttgggc actgtttaaa 5100ggaaagttcc gagaaggcat cgacaagccg gaccctccca cctggaagac gcgcctgcgg 5160tgcgctttga acaagagcaa tgactttgag gaactggttg agcggagcca gctggacatc 5220tcagacccgt acaaagtgta caggattgtt cctgagggag ccaaaaaagg taggggctct 5280cctgaatttg ggtcacctaa cagaggcagc cagatccttg aggcacctta acttcattct 5340gagcatcact ttctagcttt ccttttgtat tgcctgcctg cctgccttct gcctcacagt 5400gaagcccagc ctccttgcct gagttatgtg ggtcacaagt tgaaattcct gtggggttca 5460gcataggaga attaatcaca ctgtatgcct caatgtatat gggggggggt gcattgaata 5520tgtgttttcc agttagtctt tcaaaaaaaa aaagaaaaaa gaaaactgga taacttgtta 5580aaatttactt atctaatagt ctttagtgag tgactatttt gcagaaaagg agtaatgaga 5640ggaatatctc atcactatgc atggtaataa aactgtcaac ttttaaagtg taacatggtc 5700agctgaggtg tttattaaaa gtcagattcc tggacccctc ttttcaagat tctgaccagt 5760gtgtctggaa gagagctcag gaatctgcat ctggaacaaa tccttcaggt gacctcactt 5820gggaaacatc tggctggcgg ggtcctttat gtcacaaggc acattcgcat gccatctgtc 5880atgtatttct ttacctgtcc tgtacaactc agaccttgta gaaaaaaatc agtttaatag 5940catgaaaaaa taacttccca agggagttgc tgaaaaatac cttatttgtc aacaccgtgt 6000tatgcattct aagaattaaa tgctcaggta tttttacaag atttgacatt tagttaggtc 6060agttcctgtt tttacgttgt gccatttccc ttttccccaa acatgtagga gccaagcagc 6120tcaccctgga ggacccgcag atgtccatga gccaccccta caccatgaca acgccttacc 6180cttcgctccc agcccaggta tggtggaggg cactgggctc cctgagggcg aggctgtgtg 6240ggccagctgc ccacatggcc agagaaccac agcagcccag acagcagaac ttgccatttg 6300ctatggctgc tccaacagcc cagaaaaacc ccaggtcact gaacgaatgt ctcactttcc 6360acacggtgct gccattggtg tggattttaa gttggggagg gtcgggcgtg tccgcctgtt 6420ggaatatgct tctcaggtct tctgggaaac agatgttttg tggaagtgga agattttgga 6480agtagtgcct tatcatgtga aaccacaggg cagctgatct cttcaggctt tcttgatgtg 6540aatgacagct ttgtttcatc cactttggtg ggtaaaagaa ggcaaattcc cctgtggtac 6600ttttggtgcc aggtttagcc atatgacgaa gctttacata aaacagtaca agtatctcca 6660ttgtccttta tgatcctcca tgagtgtttt cacttagtct gatgaagggt tcactccagt 6720cttttcggat gataaaatgc ttcggctgtc agtctaataa gggattccct gaggagtttg 6780gaggctgtaa gagcaccccc cgtctcaatg ccagtgcttc ttatctcagc ctctcctgca 6840ctcctttacc cccgtctcga tgccagtgct tcctatctca gcctctcctg cactccttta 6900cccccgtctc gatgccagtg cttcctatct cagcctctcc tgcactcctt tacccccgtc 6960tcgatgccag tgcttcttat ctcagcctct cctgcactcc tttacccccg tctcaatgcc 7020agtgcttcct atctcagcct ctcctgcact cctttaaccc cgtctcgatg ccagtgcttc 7080ttatctcagc ctctcctgca ctcctttacc cccgtctcaa tgccagtgct tcctatctca 7140gcctctcctg cactccttta cccccgtctc aatgccagtg cttcctatct cagcctctcc 7200tgcactcctt tacccccgtc tcgatgccag tgcttcttat ctcagcctct cctgcactcc 7260tttacccccg tctcgatgcc agtgcttcct atctcagcct ctcctgcact cctttacccc 7320cgtctcaatg ccagtgcttc ttatctcagc ctctcctgca ctcctttagc aggttcacaa 7380ctacatgatg ccacccctcg accgaagctg gagggactac gtcccggatc agccacaccc 7440ggaaatcccg taccaatgtc ccatgacgtt tggaccccgc ggccaccact ggcaaggccc 7500agcttgtgaa aatggtaagg aggataccag tgcaggaaat agaagagcta attgctaatg 7560tggccatggg ccatggcgaa tcctggtctg tcctgggcag caccaaagct ctttcccctt 7620cttagaggct gcgtgtgcag ctcggggaga ggggggtttt ctcactcctg tgggatggtg 7680gcatcccaca gccaagttta ctctcaggat ccatgctagg cactgccctt cgtgggatct 7740tatttaaaca ccacagagat cactccaggc agtggaaaac agccccccac tttttatata 7800gagaggagat tgtggaagct cataaataat aagtagggat gctgggagat tattgagctg 7860gtatatttct ctcgaatagt ggtgtgttca ttgttgctat tgttggaatt agaggtgata 7920ctaaaaaagg aacggaaaaa taccatggca aacacataaa acgtctctac aggtgcctac 7980ctaccactgg gtcccagaaa gacttgctga ttgtggatta gatgtggtcc cctgccctcg 8040ggagttcccc agacatcaaa atgagctccc tcagcagaag ctctcattag ctgggtgcag 8100ggagaatcta gcaatgcggt aactcaggcc ttcaggactt ttgagttagt tacttaaatg 8160gaagtcctga gacaggtcaa cacactgaac cctttggatg ttttaggaat atttgttcct 8220ttgcaatttg gccttttttt ccccagtcat gttcaggtta tccttggctg caggtagtga 8280agaggtgtac cactctttaa tgtttgtact gagtggcatg ttcacaaaaa agctcagaat 8340tcagttgcat tggcttttca agagggattt gcagcaaggg ctggtttcca atatggtagt 8400ggaggaattg gctaacataa aactagctcc tgaaattcag acttgcgttt actgctctgg 8460ctctatggaa ttagtaacca tgggaaagag gcaatgctta gaactgtgta aagtgatgga 8520gtaggtagag acctgtcttg aagcatcggt aacagtaaat gaagcagcag caagatcagg 8580tgttctgtgc cacattcttt ttccattcat gtttcataca acattgtctt caggaacatg 8640gttcagtgtt ctcccaaccc acaagagaca agcaaaataa aaatggacta aataatttgc 8700tagtttttaa ttgggctctt tggcacagac tcaagtagac ctgaactctc agctctgttg 8760tgaacccgct ttgtgaacaa ggacaaagca tgtcatctgt ctctgagcct cagtctccct 8820gttagtcagt tacagagaga gcgctccaag tttccttcca aagctgtgca ctggctcgtt 8880tctccatcag ctttggtttt ccagttggtc tccagctcat ctttgcctca caagagcgtg 8940ccctgctagt tgctggtgct gggagtgggt gggaaggtga ttgggcgcca gccccttcct 9000tcccaggctt cacacacaca ccccaggaag ccccgcggtg cgtcggactc tctgtctaga 9060catcatctga tttttatttg caaatgcagg ttgccaggtg acaggaacct tttatgcttg 9120tgccccacct gagtcccagg ctcccggagt ccccacagag ccaagcataa ggtctgccga 9180agccttggcg ttctcaggtg agtgcagggt ttgctcctgg aggcaccgca ggaggccagc 9240ctctgctgcc agctctgtca tctttgggca gattcgatgg gactttagac acttgctttg 9300ctccctctgg ggtctggagt agatgtagac acatcctgtg tgtgaggtga ccagggtgat 9360ttaggagcac cattagaaaa cctgacatca ctgcttgtgg ttctgctgac cgtttcagcc 9420actggcttga atggagtcat tttggcttct tcactggcac ctctctgaat ttctaggaat 9480gtgcctttac ctttaccgag ggcccctctt cagccaacat tctcacgatg tggaataatt 9540gcttggaagt gtagaagggc ttctcatttt gagaagctga tcatccttcc aggttgagcc 9600acaaataagt cctcctcctc tactccctgg ggacattagt tctggtccct catctctaaa 9660acattgatgt gcctaagagt aatacacatt ttggtcttcc tctgaacttt aatatagctt 9720gcaaacaaat atggattcaa tctgattttt aaagttttat ttctaaaaaa aaaaaaaaaa 9780tccctgcacc atggagatct tacctactat aaagaaggca cctctaggct tggcaagcac 9840acgtgctata tgtatattta tttttcagat aatattttgg attgttttta aatgggattt 9900gtttttatat taaaaccaaa tagcttaagg tttggaattc tcatcttgcc ctctggcatc 9960tttaaaaatc agtgatgaaa aatactaact aaattctgaa ggtttcaggg aggcgagagt 10020tgtggcactt ttgctgctca gaggggagct ggagtttgac ctaccagctc tttctagttg 10080tgaatgaggc ttgcaccttt ttttctgagg tgctcgtgag taactgagga tgccctttgg 10140gaggaggtgc ttctgagcag gaaggcttgt gtttgttttt agaaactttc aaacccttgt 10200cttgaacacc taagacttgt gtgggtgcct gaagagtagg aaataaacag ctatttatat 10260ctcggcaacc tcgtgatttc tgatgacatt aaatgaaatg aaacctgccc cgagaatcac 10320ctcgaatggc caacacccac tctctttggg gcgcactgtc tgactcgctt tcagacagtg 10380tgttgaagca gagaattgag acagtgatgt gggttaagtc tcaaaacctg ctgttgagga 10440ataagatagt tttgtgggtt tctttttttg gtatgcatga tacagattaa ttatcagcca 10500tgagcacatt tattagataa ctgtgattcc cattgatttt ggggttccat acagttacca 10560gtggcagctg cctcctgtct gtgccactcc cctgcggtct ggctgaggag cttgtgcaaa 10620cccagcttgg ttctttcaac tcatgggcga tattttaaag aggcttctga aatcagcaaa 10680acgtttgtaa atggattcat cttgtttaaa gtttcagaga gcgcagtttt agagttcttt 10740tcaaacttaa acacaaagcc cagtgggaat ttcagcagac tttacatgaa cttttagagt 10800atttttctca ttaatttctt tcttttcaca agaattaatt ttgtgataaa aacaccacat 10860atccagtgtg gaaaactaat ttaaaaatca gaaaaacaaa aatggaaaat aaaaatatca 10920cattctacca cccagaaatc accattaagg cctcagtgct taccctttaa tgtgtgtatg 10980tgagtgtgtt tatatataaa ttatatagac ataaataatt aagcacctaa ttctatatat 11040aatttatata tgtacacaca cacacacaca cacacacatt tgctttttac ctaaatgatg 11100tcatgttatt attttgggga cgtttcaggt atgtggaccg acttgcttct ttctgaaaca 11160ccgttatatt ttttgctagt ataaattaaa cttagggttc atttcctcca aagtaaaaat 11220tgatttgctt aaagatgaat tttcattcag tgacacatga cttaaatgac atcaccacta 11280tcatcatcat aattcacaaa taagacttag caagttctta atagtgatgc tctataatag 11340gaattcaact tacatttcca gaaaattaat gaaagataca cttgttcctt aaaaaaagag 11400tcggtggcca catacgtttg taatatgctg gtttagacag attaaatggg tttctttcca 11460cgggacttct ccaagtgttg accgagctca tgctgtctgt ggatctctgg gggagacaag 11520ggcacgctgt gtttcccagg cctccttgac gcgggaacct tttgttcccc cacgggacat 11580gtgggacact agagttccac cacaggtgct tggctctgtg gagtcgttgg cctcgaggtg 11640gtgtccttgg cccccagcac tgactccgga gctctgtgtt tgcagactgc cggctgcaca 11700tctgcctgta ctaccgggaa atcctcgtga aggagctgac cacgtccagc cccgagggct 11760gccggatctc ccatggacat acgtatgacg ccagcaacct ggaccaggtc ctgttcccct 11820acccagagga caatggccag aggaaaaaca ttgagaagct gctgagccac ctggagaggg 11880gcgtggtcct ctggatggcc cccgacgggc tctatgcgaa aagactgtgc cagagcagga 11940tctactggga cgggcccctg gcgctgtgca acgaccggcc caacaaactg gagagagacc 12000agacctgcaa gctctttgac acacagcagt tcttgtcagg taaggcacct cgttatctgt 12060tagaatggag gtggtgatgg cctgcctgcc acaggggtca gaaaccacag ggtccctccc 12120accccaggct gaggtcttcc tcctgttgac ttcggcgccc actgggcttg gggcttgact 12180ccagtagaga tcttctgtct ggctctgttg tgggcagaga gtccggatca gatggtccag 12240gtggaccatg gctcaggctg ttctcttgca attctggttt tcagcagtcg cctcttaaaa 12300cagttccatt tcattgcact atgatctcga caaatacgtc tgctgatgtg gcggctcttt 12360tcaggttccc agaaaaatca taaaggttgg aagcatattg ttaacattct tggttgtcag 12420gtgtgtcacc ctcatgcaga tgctggccca cgagtgagac ggagggtgga gtggactgta 12480ctggttttgc acaggagaag ttataggaga gtgctataag ttggctctgt gatatgaaca 12540tttctaagca tatttttcag aaccagtgag ttttgttttt ctaccttgga tttcatgaca 12600attcagcgaa cctctggctg gcttctgtga agcccctcgc cctgtcatgc tgggcttcct 12660cactggcttt gtggggctgt ccaggtggag ggagcctccc gcgtgggagg gagctgctct 12720acccgccact cgccacccca ccgccaactc ttcctctgcc ttttcccagt cctgtccctt 12780cctgagcccc ttcagaaact cctgtgtctt tgatttctca tgtgcctccc cttttcttga 12840atgtgcttct tcattcaact tatttaaaat aaaaatatga cacgtctgtg tgctctggca 12900ctgttgacat gtgctcgtac ttctgggtgt aagtgaccca agtttttgta agctcatcca 12960gattttcttt tggtgcccaa agcaaatatg tccccagata actaagcttc aggccaggtg 13020tggtggccca tgcctgtaat cccagcactt taggaggctg aggtgggcag atcacttgag 13080gccaggagtt caagaccagc ctggccaaca tggcaaaacc ccgtctctac taaagataca 13140aaaattagct gggcgtgatg gtgggcgcct gtaatcccag ctactcagga ggatgaggca 13200caagaatcgc ttgaacctgt gggaggcgga ggttgcagtg agctgagatc gcaccacggt 13260gctgcagttt gcaggacaga gcgagactcc attgcccccc gcaccacaaa aaaataacta 13320agctcacaca gaggctgacc ataggaagag ggagaactgt gctggttccc cgaggcggcg 13380gcaagtgagg aagtcacctg gggctggaca cctctcattc taagggcaga accatcccca 13440agccctggcc agggcggtcc catccttctt ggggttgggc atggtgttca tgggggacca 13500aggaaattga agggcaactg gggggacccc ccctcccctg tcagcatctc ctgtgtctgc 13560cttgggatct ggaagagctc acatgggcca ggaaggctaa ggcccactgg gcctggattt 13620ctgaagactc tggaccttgg tgccagtgga ttcagaagat accacaaggt gagggctttc 13680taatgaaagt gtcacaagga actggcactg gcttttctga gtgcctcttg ctgggcgttt 13740ttagggaggt agagcccccg tggtgactaa gctggaaggt gcacattgag tcacaggtgc 13800actgcgtgag agacagcaca ggcagggggt ggacgcctgt gagtgtcctg gggctgtaga 13860cttgcgcgac tagaacttac tattaatctg tgagcaagag ctggtcttgg ctttcattcc 13920ttcctctgta accaagggct gtgctctttg cccactgcag cctctcacct caaagtgttc 13980actgaggttc aaggaggatg ctgtgaacgt aaaaactgca gctgtgccaa ccagcttctg 14040cataattaag gattcccacc aaacactctc atgttatcta gggttggagc catgctttct 14100cagagaattg tgccaactcg ccattctgat tagcctgtgt aggtgtagtc tcagatcacg 14160gcagtgtgaa tgtattttac agattctgac taagtcattt gggtttgatt tgaattctgg 14220aaaaaaaaaa aagcaggaag tcaaatagtc ctgtaagtta gctagaaact tctgttcagt 14280tgaagagaac agtggagatc tttgatatct tcctattcag gtctgcacag cactagggac 14340agcccccagg gcccggcccg agggtgtgta tctgataagg acgcgtctgt tctgcagaag 14400ctgtagcggc tcctgtgtca actcgtttct tttgcgggcg tgacatttta ttgtagctac 14460aggcagaaga tttgtcttgt gtacagggga gggagcatgg gctaaagtca ggggatgggc 14520acttgtcttt ccaacaatgt tccagtccgt tttgtatctt ttgggtaggt gtggtggctt 14580caggatgtac atgtgtatat ccacaagcgg gaggccaggg gggctgcccc actcctgttc 14640tcaagtcaag ttactgttcc atccctggag acaggcaaga agtctactca gagttacaca 14700gttcaggcat agtgacagtg ggactcagct gccgatggct ggtgctcagt caccacgttg 14760acgttacata ttttctgtgg tgcctgagtt acgtggatgt ccgcagtagc acagatactg 14820gattatgtgg gctctgtagt gaggggatga ggttttaaaa tgatcctggg atgtcgaaac 14880attctgattt tttaaatgaa aacttgtcca tggcataaat tggtcttttg ccattgcgtg 14940actacgtttc ttgttcttta tctcccgact tcactgtggt ctactacctt ttgaatcttc 15000gtgggtccaa tgctgcaaag cagtgttctt tagctgtcga ctagttcctc ttgaagaatc 15060gagggagacc gagggccctg gggggaaagc acccaaagga atgcatacat gctattttgt 15120atctgagatg ttcacatcaa gagccccact cagcggagta agagtgctca ttcctcttgc 15180agtgttcaga atcacagtaa gctcttgctt cctgtttaac ctggtgtgtt cggtgatgag 15240ggtttctgaa catggtctct ttcttgtggg cttctacaga gctgcaagcg tttgctcacc 15300acggccgctc cctgccaaga ttccaggtga ctctatgctt tggagaggag tttccagacc 15360ctcagaggca aagaaagctc atcacagctc acgtgagtcc tcagttacac tcctaccata 15420gtggcttcct gttctttgta aaggccagag tttcatttag aaaagtccca aatgaaaagt 15480aaatgtcaaa tgacctggaa aaataagcgt aacccttaaa ctagtgaggg aggaagcatg 15540gtccaacgag cagcacagtc tgaggactca cgtgctcctc ccagacttga gatctgctca 15600tcaaagaacc agggaggaca gcctcaaagg agggtgcctc tttccccatc ttttttattt 15660ttcaggaaag ttgtcgtatt tccattttat agggattgaa aaagattgat ggttaaagtt 15720gccctttaaa attctccagg ttaagattgc tgtaagaatg ctatctagct agtggatctt 15780cattcaatgg aaaagctttt cccaaatgag aaactatcca ttccctggag gcattttgta 15840ggtctctgca gctgtgtcct agcacctctt ttatttctgg aattttagaa attatttaat 15900tattgggcat atgatatttg aaagaggctg aatctttcaa ggaattcaag caaatcagac 15960cctctcgtaa tgttctctag catagctcaa gatgggttca actgtggcaa gtaacactaa 16020aagggtaggg ttaggattag ggttagagtt ttctttttta tgagaaaagg tttccataga 16080taacatgaag cattaatttg ccatgggaaa cagaatcttg aacccttaag acttttgaat 16140ttgaaaactt cacattgcta catacttgca agcattatta acgggcttgc atgctgagca 16200ataccaggta aaagttacac cccctaacat caaagttctc atcatgttct agctctgatg 16260ctatttctca ttgagaactg aaatgaaaca tggtttaatc

ttgaacatac aacccccctt 16320cttgatttta aaaacaaaga ccagccaacc aaccagtata taatcccata gactcaggag 16380ttttctcatg agttctctcc agtgattgac ttaataattg atatgattgt tgaaataata 16440actgatacat tgttaacaac aggaattgct aaatgactaa ataaacttgg cattgataag 16500cagcatttaa gaagttgatg atcggccggg cacagtggct cacgcctgta atcccggcac 16560tttgggaggc tgaggcgggc agatcatgtg gtcaggagtt cgagaccagc ctgaccaaca 16620tggtgaaacc ccctctctac taaaaataca aaaattagcc gggcgtggtg gtgcgcacct 16680gtaatcccag ctactcggga ggctgaagca agggagtcac ttgaacccag gagtcagagc 16740ttgcagtgag ccgagattgc accactgcac tccagcctgg gtgacagagt gagactctgt 16800ctcaaaaaaa aaacaaaaaa agaagttgat gatcagctca gctatcacat caatccagtt 16860ttaaagttga catggatgca agtcactgtc ctctaagtca gggaaagatg gatccccaga 16920tgaccccctc atgctgaaga cgaggctgcg tggtccataa aatgaataaa cacacgtgta 16980cacctatgag ttccactttt aaaaattatt aatttaattc atttcaggta cttaggagtt 17040tagcttaagt cgtcatatat aaaatacagt ctctaatatc atgattgatg gagagcattc 17100agcttgcctt agatgctgta aattcaggaa aagctgaaca ttaaggcgtt tttgtttttt 17160ggtgagtgtg atccacgcta ataaccagac agtataaatt tgaggccagt tagcttctct 17220ttttccacaa tagtagtttt gttgttgttt aactttactt tttatttctt ttacctctgg 17280ttgagaacta tacagattac ctagaaatca aatcattcag gatgagctcc ttgtttcttt 17340caaactgcag ttgtggaaaa acaaaatcat tggcctaaat taccctgcag attccctcag 17400acttcctttt aatttgatca ctttacttga tttgatgcag ttttagttaa atgtacattt 17460taagtggcag tcgatttgaa agtaacatct ttaacccaga attaagtcac tttggctgtt 17520tttttacatg ttgatctatg gaaggactaa ccaaaaaatt gcttctttag atggctccaa 17580atatgaaatg ttttgatgtg ttctaggatg taactttggg ctttacgtta ctgtctcctt 17640agaatctgag tgctgtttaa tagtgagcca gttgcaggat atctcagtaa tgtcttttta 17700aaatctctta ttaaaggtag aacctctgct agccagacaa ctatattatt ttgctcaaca 17760aaacagtgga catttcctga ggggctacga tttaccagaa cacatcagca atccagaaga 17820ttaccacaga tctatccgcc attcctctat tcaagaatga aaaatgtcaa gatgagtggt 17880tttctttttc cttttttttt tttttttttt gatacgggga tacggggtct tgctctgtct 17940cccaggctgg agtgcagtga cacaatctca gctcactgtg acctccgcct cctgggttca 18000agagactctc ctgcctcagc ctccctggta gctgggatta caggtgtgag ccactgcacc 18060cacccaagac aagtgatttt cattgtaaat atttgacttt agtgaaagcg tccaattgac 18120tgccctctta ctgttttgag gaattcagaa gtggagattt cagttcagcg gttgaggaga 18180attgcggcga gacaagcatg gaaaatcagt gacatctgat tggcagatga gcttatttca 18240aaaggaaggg tggctttgca tttcttgtgt tctgtagact gccatcattg atgatcactg 18300tgaaaattga ccaagtgatg tgtttacatt tactgaaatg cgctctttaa tttgttgtag 18360attaggtctt gctggaagac agagaaaact tgcctttcag tattgacact gactagagtg 18420atgactgctt gtaggtatgt ctgtgccatt tctcagggaa gtaagatgta aattgaagaa 18480gcctcacacg taaaagaaat gtattaatgt atgtaggagc tgcagttctt gtggaagaca 18540cttgctgagt gaaggaaatg aatctttgac tgaagccgtg cctgtagcct tggggaggcc 18600catcccccac ctgccagcgg tttcctggtg tgggtccctc tgccccgccc tccttcccat 18660tggctttctc tccttggcct ttcctggaag ccagttagta aacttcctat tttcttgagt 18720caaaaaacat gagcgctact cttggatggg acatttttgt ctgtcctaca atctagtaat 18780gtctaagtaa tggttaagtt ttcttgtttc tgcatctttt tgaccctcat tctttagaga 18840tgctaaaatt cttcgcataa agaagaagaa attaaggaac ataaatctta atacttgaac 18900tgttgccctt ctgtccaagt acttaactat ctgttccctt cctctgtgcc acgctcctct 18960gtttgtttgg ctgtccagcg atcagccatg gcgacactaa aggaggagga gccggggact 19020cccaggctgg agagcactgc caggacccac cactggaagc aggatggagc tgactacgga 19080actgcacact cagtgggctg tttctgctta tttcatctgt tctatgcttc ctcgtgccaa 19140ttatagtttg acagggcctt aaaattactt ggctttttcc aaatgcttct atttatagaa 19200tcccaaagac ctccacttgc ttaagtatac ctatcactta catttttgtg gttttgagaa 19260agtacagcag tagactgggg cgtcacctcc aggccgtttc tcatactaca ggatatttac 19320tattactccc aggatcagca gaagattgcg tagctctcaa atgtgtgttc ctgcttttct 19380aatggatatt ttaaattcat tcaacaagca cctagtaagt gcctgctgta tccctacatt 19440acacagttca gcctttatca agcttagtga gcagtgagca ctgaaacatt attttttaat 19500gtttaaaaag tttctaatat taaagtcaga atattaatac aattaatatt aatattaact 19560acagaaaaga caaacagtag agaacagcaa aaaaataaaa aggatctcct tttttcccag 19620cccaaattct cctctctaaa agtgtccaca agaaggggtg tttattcttc caacacattt 19680cacttttctg taaatataca taaacttaaa aagaaaacct catggagtca tcttgcacac 19740actttcatgc agtgctcttt gtagctaaca gtgaagattt acctcgttct gctcagaggc 19800cttgctgtgg agctccactg ccatgtaccc agtagggttt gacatttcat tagccatgca 19860acatggatat gtattgggca gcagactgtg tttcgtgaac tgcagtgatg tatacatctt 19920atagatgcaa agtattttgg ggtatattat cctaagggaa gataaagatg atattaagaa 19980ctgctgtttc acggggccct tacctgtgac cctctttgct gaagaatatt taaccccaca 20040cagcacttca aagaagctgt cttggaagtc tgtctcagga gcaccctgtc ttcttaattc 20100tccaagcgga tgctccattt caattgcttt gtgacttctt cttctttgtt tttttaaata 20160ttatgctgct ttaacagtgg agctgaattt tctggaaaat gcttcttggc tggggccact 20220acctcctttc ctatctttac atctatgtgt atgttgactt tttaaaattc tgagtgatcc 20280agggtatgac ctagggaatg aactagctat gaaatactca gggttaggaa tcctagcact 20340tgtctcagga ctctgaaaag gaacggcttc ctcattcctt gtcttgataa agtggaattg 20400gcaaactaga atttagtttg tactcagtgg acagtgctgt tgaagatttg aggacttgtt 20460aaagagcact gggtcatatg gaaaaaatgt atgtgtctcc caggtgcatt tcttggttta 20520tgtcttgttc ttgagatttt gtatatttag gaaaacctca agcagtaatt aatatctcct 20580ggaacactat agagaaccaa gtgaccgact catttacaac tgaaacctag gaagcccctg 20640agtcctgagc gaaaacagga gagttagtcg ccctacagaa aacccagcta gactattggg 20700tatgaactaa aaagagactg tgccatggtg agaaaaatgt aaaatcctac agtgaaatga 20760gcagccctta cagtattgtt accaccaagg gcaggtaggt attagtgttt gaaaaagctg 20820gtctttgagc gagggcataa atacagctag ccccaggggt ggaacaactc tgggagtctt 20880gggtactcgc acctcttggc tttgttgatg ctccgccagg aaggccactt gtgtgtgcgt 20940gtcagttact tttttagtaa caattcagat ccagtgtaaa cttccgttca ttgctctcca 21000gtcacatgcc cccacttccc cacaggtgaa agtttttctg aaagtgttgg gattggttaa 21060ggtctttatt tgtattacgt atctcccgaa gtcctctgtg gccagctgca tctgtctgaa 21120tggtgcgtga aggctctcag accttacaca ccattttgta agttatgttt tacatgcccc 21180gtttttgaga ctgatctcga tgcaggtgga tctccttgag atcctgatag cctgttacag 21240gaatgaagta aaggtcagtt tttttttgta ttgattttca cagctttgag gaacatgcat 21300aagaaatgta gctgaagtag aggggacgtg agagaagggc caggccggca ggccaaccct 21360cctccaatgg aaattcccgt gttgcttcaa actgagacag atgggactta acaggcaatg 21420gggtccactt ccccctcttc agcatccccc gtaccccact ttctgctgaa agaactgcca 21480gcaggtagga ccccagaggc ccccaaatga aagcttgaat ttcccctact ggctctgcgt 21540tttgctgaga tctgtaggaa aggatgcttc acaaactgag gtagataatg ctatgctgtc 21600gttggtatac atcatgaatt tttatgtaaa ttgctctgca aagcaaattg atatgtttga 21660taaatttatg tttttaggta aataaaaact tttaaaaatt tgtta 2170592139436DNAHomo sapiens 92agtagggagg tgggcaggag ccagtgatga cggaatggca atcacatttg acctctgatc 60tgtttatttc ctcctccttg acgtctccat ataaatgtta cacgggcatc cccacactcg 120gatacgcacc cacagtggct gattcggggg taaccgtgtc atttgcttgc aacactggca 180cctctgccct gcaccccggg agtgagcagt gagtgaggct cgggtctggg cgctggctcc 240gaatcttcgg gctgggagag actccaccat ctgggggcgg cctgggggag cagccttagt 300gtcttcctgc tgatgcaatc cgctaggtcg cgagtctccg ccgcgagagg gccggtctgc 360aatccagccc gccacgtgta ctcgccgccg cctcgggcac tgccccaggt cttgctgcag 420ccgggaccgc gctctgcagc cgcagacccg gtccacacgg ccaggggcta cgacccttgg 480gatctgccct ccgctcagct cgagcttccc tcgtggccga cggaacaatg aaggtaacta 540cttatggttt tgtccgtgtt ttacaaaaat gtgtgcgtga atcgaaccgg cgatttctcc 600aagaaacata gttggcaggg aggggaggaa ggcgagacaa ccatggctta tatcccccgc 660aaacgtctca gtatcttctt tatcaatcgt agtttgcggg gaccgtgcat tctgttcaga 720tttcggttta acctccactc gcaggacgtg ccttctcgga ctttttcaca ttcgcttttg 780ggaacggagg tgaaagtctg ctacagctcc ctcccctgct tgtgaagttt ggaaaggaag 840tgagggcttc tctcagtttc tcctatgcac aggaggtggg gaattttgga gaggaggtct 900ggggatgtcc cgggctgtaa atgcgctttc ctgcagcgtg tgttcgtgat gcaggaggga 960gcggctggaa gagttgaccc gggtggagag gggagggaga acgatctttt cactgttaaa 1020agcagaaggc ccctcttatt ttgtttcttg tggaaattaa agcttctagg agttacaaat 1080gatagacgcc taagggcatt catttgttaa accagtgagc accctaatgg ctctgatctt 1140gctaatcaag gataattagc ctagctgcct attatttctg actatttagg tgtagggatg 1200tacaccgttg agtgttttgt tttcctagtt tcacacactg gaaaactgca atcgcatata 1260aaacccgaag agcaactttt tccaaggaaa gtgaaggatg ggcagatatt cttgccatct 1320aacattttgg aattgagatg accataatgc aatctgaact tctggtagga ataaagcctc 1380gtttcagagt ttctaaggag ggagatgaag cgtggttctc aactgctctt atctacaacc 1440catcccagac catagtttca cttagaagaa ataatatgta aatagcgcct ttgttgccaa 1500acaaaaactt tcactacaat taaacagtaa ccgagtggaa actatgcgtt tttgtattca 1560acagagatca cacaactttt cttctatagt tagaggttct atttctggct tcctcatgct 1620tgtttcattt cagatgaaaa acacacttta gttgattata gctttagtaa gtaaaaggag 1680aaaactaaga atgaacagtc ttgcttttcc agctttttcc tgtccatgtg cagttgtggt 1740taattacgcg tttttgtagg tccaaaaacc cctgtccctt ccacaagata cttttataac 1800atggggaact aggtaagata tctacaagta gtctcttttc tgtttcctga tatttcctaa 1860gattaagaaa gaaatgattg tattctaggt atgatcgaag aagtatggaa ggttccatta 1920agttagtttt atcacaatat ttcaaacatc tttccactta tctcttaaat atgtattgct 1980atcacaagct tgatttttta aaaaaatgtt atttgcacat ggcatcttga ttgcctttgt 2040cctcagcaaa ttctccgggc ttaagtcatg catgagcttg tattttaaga cagacacatg 2100cagaatgggc aacttggata agaaacatag gatatacact gagtagcatg tgtacaaaaa 2160tggtaagtga gtattatgac ttaataaatt tagatgggga tttaaaaatg atacacatgt 2220aaatgggatt ggaggcaagg gaagtccgtg tgtgtgtgtg tgtgtgtgtg tgtgtgtgtg 2280tgtgtgtgtg tggagggaag acgggaggcc tagtggggag agaggtttta cattccagac 2340acaggatgtg gcccctcagg ctaggctcag agatgtaaag ctagttaagc tggcctaaca 2400aaagggtggt ggttagaaaa aggaaaaaaa gaggtggggg ttggggagga aaagaattta 2460atgctggcca atattttcat ctgataagtt tcagtaatga gtaatttcac tggatttcag 2520aactacagag agaaaagggg aaaaatattt ttcctttttt acgcaagaat ttctcttgct 2580tttcagctca ttagaaccag atctaattat ttgaaatgag tttaaaacct tattatgaaa 2640ggaagttgaa aacattcgat cacaattgag ttttgtacta tggactaaaa ccaagatgtg 2700ctttctgtca gtagctgtgc aactccctga aaaaagaaaa atagcgcaga gcgatctgag 2760ctttgtgaag gctacacaat ttatcaggcc cagagagata ggagtgtgag acttcagtca 2820cgtccccccg tacgcatgcg caggagtaat tatttaaaga cattttgttc ctgactaact 2880gcctcactca ttatgttcct ggaatttgtg atacaaaaaa acaatgttta gcctatcaat 2940agtttatata gtttatgtta ttttaatata aattcttctc aacttagaaa ctgcctcttt 3000tttcttttaa aaacccactt gtaactgctg tatatattca gggcaacttg atttggtgtt 3060tcgttggttg cagtcctcaa atttgacctc aatatactct ctacttatat aaattttgtc 3120tcagttttgt ccgtaggctg acattccaat tgttttccta attatatatt ttgttcctta 3180tttctcatgt ctagaaataa agctagggaa gtaaacagct ggaaaactga tagtggtgtt 3240attaacctaa ctgagagggc tgggcttatg agtaaattat tcctgtgcat aaatgaaaga 3300ttgtttctaa atggcagcta tgttgagcct ttgtattagt tacatctttt ggggtttcag 3360gttgccagct tctttaaatg gcctcttctc aactggtata ggaagttgga aaataaagaa 3420ctttctttat ttccctttag tgttggtaac cacagtttct ttaaataaca gatgcccacc 3480ccagggaaac ccagtggcat gatcagcctt atgctcagga aggtttggtt gctatactgg 3540agagtgagaa tctgggacct tccatgatag acataattgt gccagctatc ctctactttc 3600tatatgatgc tatcattctt ttttcttttc ttttttttga cagaatctca ctgtgttgtt 3660caggctggag tgccgcagag tgatctctac tcactgcaac ctctgcctcc taggttcaag 3720caattcttgt gcctcagcct cctgagaagc tgggattacc accatgccca gctaattttc 3780gtattttttt gtaaagacgg agttttgcca tgttggccag gctggtctgg aactcctggc 3840ctcaagcgat ctgcccatct cggcctccca aagtgctggg attacaggca tgtgctatca 3900ttctttttga gcacaggagg aaactatggc tgatctgctc attttactgt caaaaatata 3960ggcagctttt gtattgtaac attatcccct taacagctgt ccaactggtc tatacatttc 4020acctaacata tggtaaatgt tcctactgtt ggcctttcct gagcctctgt ccattcaact 4080aaggccactg caatgggatt gtatgcagtt cagccaagaa ataaatgtga ggtgcaactc 4140acatttttta aatgtttcaa aattaagcat ttaggtgctt ttattcataa acatgacttt 4200gcaaatattg gtaaacagtt tcatcataag accttgtcag tgactcacaa tgtcaatggt 4260gaacgcaaag gagaatctgt cttttctgga acaccaggtt caggtatcag tttcaactat 4320gcttataatt tgtgctctaa agtccacaaa gctaaattat ctttccccta aaaattgagt 4380actcatatcc ttaaaatagc ttggaaatta gattacctta tgaatacagc atagcatgtc 4440acataaacgt ttttctactg ttataccttt ttggtgggaa agactatttt gcaaaacatt 4500tttcttgtgt tcagtaatta atgggaaaaa caaactctaa aagaaagaga cagttatgtc 4560ccaaaaatac aggaaaatgg aagaatggaa acagggaaga ccaataaaga aaaaaataga 4620ggaaattaca agtaataaac tgaagtcata ctgaaaaaca tatggctctt tcttattgaa 4680agttgtgaaa tacttgcaaa actcagctag ttccattaag aatagtcttt aatctaaaaa 4740gaacaaattc atttgtcagt tctttatttc ggtgtgtaga tttgaatgtt tcatcaattg 4800catttacggt ttatccctca gtgtgagaac tgtttttgct gttttgacta taaatggata 4860tctgctttag gaagacttag gaagcctggg acataggatt acagatcaaa ttctatttga 4920ctccatagaa gttgagacgg aaggagcacc tgttgggata ttctagacca aacattccac 4980agctgtctct taacgtgact gacaaagaga cacagttgag acgaagtttg ggtatatcct 5040gggatgaggc caagggtgga tttgcacagg atggtcacag ggcagttgtt agcattccac 5100cactacataa aagggtgatt ttgccaagtg catttcattt catttcagtt gatttagata 5160ccaagttata ttgttttgac tttaggacta gatgtgagtt caggaatttg aaatcataat 5220aaatgtttcc ttgaactttg aagataaaag gtagagttaa aagacagctg cgaagtctac 5280atggggaagc ataatacatg actcagggtt ccatggtttt cagtgtcggt gagtgctctg 5340tacacttata agaatagtgc tggtgtttat agaagaaaca catgcaggtt tgaggcaaga 5400cttccttgct taattggtgc ttttgctttc cattttctaa atgccatgca aactactttt 5460ttttttttct tttgttgaga cggagtcttg ctctgtcacc caggctggag tacagtggtg 5520cgatctcggc tcactgcaag ctccgcctcc tgggttcacg ccattctcct gcctcagctt 5580cctgagtagc tgggactaca ggcgcccgcc accacgcccg gctaattttt tgtatttttt 5640gtagagacgg ggtttcacca tgttagccag gaaggtcttg atctcctgac ctcgtgatct 5700gcccgcctcg gccacccaag gtgctgggat tacaggcgtg agccaccgct cccggcctca 5760aactacttta actgaaaaca ttcttctaag gaaagcatca gaaaacttac tagaattgct 5820taagaataaa taaataatac aaataaaaga gcaaaatgag aaagtagaca gactcctagt 5880ctattgtgct attgatctct ccaggttcta ggctttcttg ggtctgacac cactttgtaa 5940attttttttt tttttttttt ttttttccag atagggtctc attctgtcac ctaggctgga 6000gtgcagtggt acaatcatgg ctcacttcag cttcaacctc ctgggctcaa gtgatcttcc 6060tgcctcagct ccctgagtag ctgggaccac aggcatgtgc caccacgccc ggtgaatttt 6120tgtatttttt gtagagatgg ggtttctcca tgttgcactg gctggtcttg aactcctggg 6180ctccagtgat ccacccacct tggcctccaa agtgctggga ttacaggcat ccgtcactgc 6240actgggccag tttgtaaatc ttatgaaaag tatggccaat cttttgcaaa atgtgcaaac 6300acatatagac acaaagtttt atatctaaat tattggttat taaagccagg acaatagagt 6360gcatatagca tggaagacag gtagaaaaga ctgaaatggt ttagttattc agagcagtgg 6420agggctattg gctcttgcct ttgcagtcag ctgagatatg aaactatata agcagaagct 6480tcacgctgcc atttgaatat tgaaaatctc cacttttagt tcaagagata aacaaccaat 6540ggtttgtttg ttcacagcac ataagttatc actttcttct ctgtttcatc ccatcaagat 6600ctaaggtgta tagttacaga atagaactcg gttcatacca tatgcaccct aatttcttcg 6660atcttcaact agtttggaag tgtgtgtggg tgttttctta gccaaggtta atatgcaatt 6720tcttagtgga gtgtaggagt ttggggtgcc tagccttcct acttcccact tagataactt 6780cccctacctg ttgtacctgt caaaggagaa ggccagtatg gccatgttct ttgcaggtga 6840ctccacctta gccacagctg attgtaacaa gggtgtatat ttggcccaag tccagccatc 6900tttttttttt ttttttgagg cggagtcttg ttctgtcacc cacgctggag tgcagtggtg 6960tgattttggc tcactgcaac ctctgcctcc cgggttcaag caattctcct gcctcagcct 7020cctgagtagc tgggattaca gacacccacg accacgcttg gctttgtatt tttgtatttt 7080tagtagagac ggggtttctc catgttggcc aggctggtct agaactcttg acctcaagtg 7140atccgcccgc cttggcctcc caaactactg ggattacatg cccagccagc catcttttac 7200ttctttctta ttctcttatt ccacatattc aagcaggtac cacgtcctgt ggactctgtc 7260ttctctgaat ctataggttc tctctttccc attgccctgc atactggttt atgctctcat 7320tacttctcgc ttgaattatt ccaaaagtct cccaactggt ctgaagctta attttcatta 7380tgtgctgttc gatgtcattc caccacgcaa aatctatggc ttctccattg tctcctgagt 7440ttagtttagt gcatgagacc gtttaaaatc tacctacacc tcttctatgt gcatgcattt 7500ctctagtcat aagagaggat ttgatctatc tcaaaatgtg ttcttatatt tgcatttact 7560ggtttttaac tccctccatc ctatctataa tttgcaccat gttgctcacc atgcagccca 7620ctccccagac accttgtgag aacagtgatc atgtttttgc agtggaatga acatgggcga 7680aaggtgggaa ggtatgcata gatttacatt ttgaagtcag gaaataagat actgatcaat 7740gctttaattc gactgtgctt tttacctttt cctctgttgt agcatgaacc ttgccccaaa 7800aagatattga tcatatgctg caactcctct gcacttacct tttcttctac catggcagga 7860accttgcacc attgttggtg ctttacagat attggttgag ttaaatcgag agcctatttc 7920tggactttca agattcagat taattgattc tgttttatac ttctctgttt ttgaatggca 7980catacatctt tccacacttg gatttctttg aagttaaagc tttaattgac ttccaaaaga 8040cagaggatta taaaaacaca gagaacagta aagtatttac acggtcttaa tgcctattgc 8100caaacacata tagctgctat taatgcctat tgccagactc atatagctgc aaactcatgt 8160agcttaatgc ccattgccaa actcatatag ctgctatata tgtctactgg aaaactcaca 8220tagctggttg attttaaatt gattgtagga aaattcatac aaaaagatgc tacataggaa 8280tataaactga acaccacaaa aatcgtaatg aacaaactca gtaatgccag cctgttcaat 8340cactagtttt cagattaagg cagtatgcaa agggaaacat ccttggaatg gtcttagaat 8400atagaacaaa gtcatgtgtt tgggaatctt aaccaattcc aatactgttc aacatgtttt 8460tctttgttgc aaacaatgca gtttttaagc aaactaatga atgcataccc tgacaaacaa 8520atccaacaaa agaggtactt agagcagtgt tcattgaatc ctagaatttt gaaagaaaaa 8580atctattagg tcattttggg cttttacttc tgctgaagaa ggattgttct tttgagttta 8640tttttctagc tttcagttct attccattta aatgcctcga gaaataggac ttctcaaatt 8700ccctgtggag agttctggca cctactatat tcacttttga aagtctcctg ataactgatt 8760tcctttttct tttggttata cacatcaact attcatggtt ggctctgctg atagttttcc 8820atgattcttt atgcttattt aaaagaaatc atataacatt aatcatataa catataacca 8880ttacttggtt ataaagcatg atattaacta aactggcttt taaaaattca ataacattag 8940agcaaatatt ttattaatat tgtcagtagt tccatgaata tatagatgta ggatgtcaat 9000aaagtttatg ccccttaata actgagtgtg ttaatgttgt atttgctggt taactggcac 9060cttccctcct tttgatcaat gttcttagaa cagtatgtac aggagtactt tagtctacca 9120cttgatattc aaggacaaca cttcgaagct tgaaatgagg gattgtttta accatattaa 9180cgtaactgca tagtttgcaa tagatttaat gattcaacat cattgttaat atttagttta 9240attaaaagtg ccttatatta acttgtacac atgtgaaatg acttatcaac aagattattt 9300attgcagcat tgtttgtgat tacaaagagt ggaagtcatt tgcatagtca ttaggcgtaa 9360aaaataatga cattaaaaga aaacaattga ggaaagaacc agtaagctct caggtagaga 9420taaaaagaaa gttaccgtga gccttttcac tgtatatatt tatatatttg atttttgaca 9480cgtgagttta ttataatcaa gattgaatga aaaaaattga agccttttaa tgaaattagc 9540ttgacaccag agtcattatc aagaaaatct gaaatactgg tacctatgca catttgattt 9600tattattttt

agttttatta ttttttgaga cagagtcttg ctctgtcgcc cagactggag 9660tgaagtggtg tgatctcagc tcactgcaat ctccagcctc ccaggttcaa gcgattctcc 9720tcagcctccc gagtagctgg gattacagat gcctgccacc atgcttggct agtttttgta 9780tttttagtag tgacggagtt ttgccatgct ggccaggctg atctcaaact cctgacctca 9840ggtggtccac ctgcctcagc ctcccaaagt gttgggatta caggcgtgag ccactgcacc 9900cggccattta agcaaatttt agttaagacc agtaacatat ttttgacagt atttccgaag 9960tgttgtattt aatttaacta attgaaaatt atctattaag aaagcaagtt aaatgtaatg 10020tgtatacttc atagtataca cattataatg attcatagta accattatat gaagagtgtc 10080taaacttttc ttcaaatcta ccatttatat agtacaataa tgaccagcaa acaatggcta 10140agttttactt aattagacat ttgtgtagct cctaccaagg ctaccagact ttgtacccag 10200taacaggaaa acagaaataa ttcaagcatt attctcactc ttgagaaaca attctattta 10260gggagatata cataaaaagc aaaggtggct gggtgcagtg gctcatgcct gtaatcccag 10320cactttggga ggccaaggca ggcagatcac ttgaggccag gagttcgaga ctagcctgac 10380caacatggtg aaaccctgtt tctactaaac atacaaaaat tagctgggtg tggtggcatg 10440cacctgcaat cccagctact gggcaggctg aggcagataa ttgcttgaac ctgggaggtg 10500gaggctacag tgagctgaga ttgcaccact gtactccagc ctgggtgaca gagcgagact 10560ccatctcaat gaataaataa ataaataaat aaatagcaaa ggcaataatg tgcatatagt 10620aggtgctaca gtagaagtct gcacaaggtt ctgtgtatgt ggaaaagaca agtcagaaaa 10680attaggaaag gctttattgg gaggtgacat ttaagcagaa tcacgaaaga agacctgatg 10740aacatggggg taagagcact tgtacacaac cccatactcc tgggctcaga ctcacttgct 10800cattccctaa tcatagaaga ccttgaggaa aagcatgctg gggttccctt ccagcccact 10860ggtaaataca gagaggccta agcacccaac atcccccagg gaatacacca ctgggactta 10920aagcattggc aacccagcac ccagttaaat tccccttgtc actgtttcca cattgtcccc 10980atcaccttca ctctcttgat gctctgcatt ttctctctta actcgaccca cagtagaccc 11040tcccactcaa atctgccccc aataaccttt gcaaccaata ttaccgcact acactttatc 11100ttccctaagg gtttcctgct cctcctggtc ttaggtgagg tcatttctct gccagccttt 11160aaagtggaag ctgctcattt tctctgtccc tcatccaggg ctggagtggg actgatgccc 11220ttcaccctgc ccagtactgt ttccacatga gactccttgc atagcatctg ctctctgcta 11280ctcagaccag gagtctgtgc tctctcttcc tctaaccatc attggaagac accccagtcc 11340ctctggcccc attatccact gtagatttta gcacttacct cctctcttcc ctcccatgtg 11400ctgttttccc atttatttta aggtgcatgt ggatggccca ttccccttcc tggcatctta 11460atccctttaa tttctcattt ccattaattt gctacattcc tcatatgcca gctaccccta 11520tggccatatc ccagaccttt gaatcacaca ccaaattcca tcaagtccta tgagtcattt 11580ttggtccaag acctatctta catctatgca gtgctatcta ttttaacaac catgtgccca 11640gtttaggcca ctgtcttctc ttcactgaat atatgtgttc ctgttttttc tcatccccat 11700ttgtttccca gacacaattt gttctccaga gcagagtgat cacatcagtc acctgctata 11760aaaactcctc aacccggtgg ggcatggtga ctcacagccc cagcactgta atcccagcac 11820tttgggaggc tgaggtggga ggatcacttg agcacaggag gagctgaagt gatctgtgat 11880cacgtcactg cactccagcc tgggctacag agtgacaccc tatctcaaaa acaagcaaac 11940aaacaaacaa acaaaaacca acaaaaaatt ttttattaag caaaaaacct cttcaacctc 12000ttcctgttat gttttgaata aaagctaaag tccccaccat gctccagaag ttcccaaggg 12060atctggtcct tctcatcttt acagcctcat cttgttttgc cgtttccacc tccctcatcc 12120cccaaactct ttttcttcag ggcctttgca cttgctgatg cctctgcctg gaaggtcttc 12180ttctgattcc ccatccaggg gtgccttatc accctgccct gccaacctca gattggatgc 12240tacttcctca aagagaccct tgggactccc atgtttccca ggctttcagt gccctcatct 12300caacttgtaa tgattgtatt ggggtgatta tttgtatgac tttgggattg atatctgact 12360cttccactag accatacatt tcttgagagc agagagcata tccagttttt ttaccactgt 12420gcaaccatat gtcgtccaat gcttggccca taataggggg ttggtgaatg tggtaggctg 12480agtcatagcc cccaaggatg cccatagcct catccccaga agctttcatg gtaaaaggga 12540ttttgcagat tgtgattaag ttatggatct tgagatggag agattatcct tgattatcta 12600aataggtcca atataatcag tagcgtcttt ataagagaga ggcagagggt caaaagcaga 12660atcagagaag gagatgccac agtggaagca aaggggtgtg tgtgtatgtg tgtgtgtatg 12720tgtgtgtgtg tgtgtgagag agagagattg agatttaaag agctccatta cttgatctga 12780ggataaggat gagccaaaga atgcaggtgg cttgtagaag ctggagaagc caagaaaaca 12840ttctcactct agagcctcca gaaggaatgc agctctgctg acaccttgat ttggaacttc 12900cagaaccata agataataat tttgtgtagt tttgaggctg ggctcatgcc tgtaattcca 12960gcactttggg aggccaaggt gggtggatca cttgaggtca ggagtttgag actagcctgg 13020ccaacatggt gaaaccctgt atgtactaaa tatacaaaaa ttagccaggt gtggtggtgc 13080acgcctatag acccaactac ttgggaagct ggggcaggag aatcacttga acccgggagg 13140tagagattgc agtaagctaa gattgtgcca ctgcactcca gcctgggcta cagcgtgaga 13200cttcgtcaga aaaaaagaat aattttgtat aatttcaggc cacaaagtct gcagtcatct 13260gttacaacag cagtagtaca cgaatacaga ttttggtacc tggaaatggt gtgctactgt 13320aacagatacc taaacaatgt ggaagtggct tttgaattgg gtgttgggca gcatgtggaa 13380gaattttgag aagcatgata ggaaaagcct agcttgcctt agaaagactg ttagtagaag 13440tagggatgtt aaaggcgctg ctggtgagga cttggaagtg aagagcatgg taaagaaaat 13500gtgtttcatt ttagagaata tcaaagtcat tgtagaaggt tggcagaagt gtaggttttc 13560ataatgtgtt gttggtgagg gctgagaaag aaatgaggac catgtttagg gaaactggag 13620gaaaaagatc cttgtcatac agtggaatga aactgtggaa ttgtgtctta cagttatatg 13680ggaagcagaa tttgtttgaa cttggatatt tggcttagct ttccaagtaa agtattgaag 13740gtgtagcctg gttttctctt gctgttttat agtaaaatgc ccgagaaaaa gggataaatt 13800gaggtaggaa ctgttaagaa aaaggaacaa agacatgatg acttgggaaa ttctcaggat 13860acctggtttg taaaagatgc tagaattaga agattcattg tcaggaaagt gtgctctgga 13920gaggaagcca agggtgagtt ccttgtggcg taggttaggg gctgtggcag ggatgcaggg 13980aagagatgat ggtgacttgg actaggggtc tgacggggta tgggaaaata gagaggaatg 14040agttgattct gttgggactt tgtattgagt tccttgattc cataagtgga aacacatgta 14100gagctctctt tcctggccac ctaagctctc tgaccatatc cctgactctc tccagaatgc 14160cttggcttca tgtccacgtg aggacaaatc atatttttct gcattttgcg tgctggattc 14220ctctctggac taaagatcca atgagaggtg gtttctagct ttctgctctt tcccacaaca 14280ctccgtcagt gagtcttctg gatgtcctat aggcaactca ctggatccac ttggtctgtg 14340gaagaatcac taccacatcc atttcacctt gggcacagac tagaaggtga ggcagtcatg 14400tcctgcagtc actgggtagc ttacaagtgc taatacagca atagcttaat tagagagaga 14460gagaagaaga agaatgttat ggagcctgtt tctagagagg aaaccacaat atcttgatca 14520agagacccta aaactggaag aaccagagca gctggtatca aaatgtggaa aaaactgaga 14580tgtggcaagt ggtacaactg atagccaagg aggaaaaatt tgtatccccc tgtaatccca 14640gcactttggg aggctgaaac aggtggatca cctgaggtca ggagttcgag accagcctgg 14700ccaatatggt gaaaccctgt ctctactaaa aatacaaaaa ttagctgggc gtggtggtgt 14760gcacctatag tcccagctac ttgggaggct gaggcaggaa aattgcttga acctgggagc 14820agaggttgca gtgagccaag atcgcaccac tgcactccag cctgggtgac aagagttaaa 14880ctctgtctca aaaaaataaa aagaaaagtt tgtaccctct tcttttctct tgcctcagga 14940taactgagat tcttataatg catttattga acaaatattt gaggagtact cattatgtaa 15000gcatcagaca ctgctcaagg tcttgaggct gtgagggtgt attagtccgt tttcacactg 15060ctataaagaa ctacctgaga ctgggtgatt tataaagaaa agaggtttaa ctgaattaca 15120gttcatcatg gccagaaagg cctcaggaaa cttacaatca tggcagaagg tgaagaggaa 15180gcaaggcaca tcttacatgg tggcaggaga cacagtgaga agggagaagt gccacacttt 15240taaaccatca gatcttatga tgatatagga gttaagaaga aatcacttag gtagatagtg 15300agggtacggg agtccttggt aaggcttttc ttttaaatga aaagcagccc cacacataga 15360caagcaagct gggagcttgc acgggtgaat gccggcagaa actaggaacc agacacgtta 15420agatggcggc tccattttcc cttctctgcc agccaagtgt acagtaagga gcagacaagc 15480tggtgccggc caagaggaga attcatgtgc ataataagat tagggtgggg tgaccagcct 15540tcccagtgcg ctatgtgaac atcatacctg attgaaccaa tctgtgagcc ctatgtaaat 15600cagacaccac ctcctcaagc ctgactataa aatctggtgc attcgccacc cgccggtgtt 15660tcctctcaga agtcccctct ctctcattag agagagggct gttttccttt ctccttcttc 15720tgcctattaa cctgtgctcc taaactccct gtgtgtgtct gttctgaatt ttcccggcat 15780gagaggatga acctggggta tataccccag aaaacatagc cacttaagtg agaactcact 15840cactattcac ccccaagatc caatcacctt cgaccaggtt cctcccctgg cgtgagggga 15900ttaaaattcc acatgaggtt tgagtaggga cacagagcca aaccaaacca tatcagaggg 15960tgaagagcag gtaaagttgc agctctcctg caacttgcag ggaaaggcca tataacacat 16020ggttatgagc acaaactggg actggactgc aggtgtgtga gccccagctt tgctattgag 16080tgaccaccag caagttatta aactgtgcct cagttttttt gtttatgaaa tggtggtatt 16140agtacaaccc acctctcatg gatgatgtga ggattaaata aaataacatg ttgccaggca 16200cagtggtgca cacctgtaat ctcggcacat tgggaggctg aggcccgagg gttacttgag 16260gttagaagcc tgagacctgc ctggccaaca tagcgaaacc tcatctctgc ttaaaataca 16320aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa ggccaggcgt ggtggctcat gcttgtaatc 16380ccagcacttt gggaggccga ggcgggtgga tcacaaggtc aggagtttga gaccagcctg 16440gccaatatgg tgaatccccg tctctactaa aaatacaaaa attagccaag tgtggtggtg 16500ggcacctgta gtcccagcta ctcgggaggc tgaggcagga gaatcacttg aacctgggag 16560gcagaagttg cagtgagccg aggttgcgcc actgcactcc agcctgggcg acggagcgag 16620actccatctc aaaacaaaac aaaaaaacca aaaaaattaa ccaggcatgg tggcacacac 16680ctgtaatccc agctactcag gaggctgagg caggagaatc acttgaaccc aggaggtgga 16740ggttgcagtg agttaagatt gtgccactgc actccagcct gtgcgataga aggagacagt 16800ctgcaacaaa gatccaaaaa caaatataaa gcacttataa cagggtctgg tctgaaataa 16860gtactatgta agtactgtaa gtattaacta atattattac aatttatcct catatagtaa 16920catatcaaat attttcagtc agtgatgcaa tatgaataaa atgaaatgat gcagtagtga 16980cagaactgag agaaagctgg tacaaattta tactgactgg tcagggaaag cttcacagaa 17040aaggtgaact ttcagctgac acctgagtac catggtctgg aggtaagagt gtcccatgca 17100tatggaacag caaatgaaac ttcccagagc ataatctgag aggggagatt tcaggagtgg 17160agccacatca ttgaagttcc ttagtcctgg taagtgtgga ttttattcta agtgtggtga 17220aatgcccctg agaggttttg agtagtagat ggaattccat ttttaaaagt cactggtgag 17280tcaagtagtg tactatggtt acattttttt ccccttatac ctcattttgt ttttcctgca 17340gttaattctt gcattatttc cttttattta cttaccttac tatatattta ttatgaattc 17400tttccaattc ccaacttcct gacagcctct caatgtaatt ttacttaggt taaatgtatc 17460tgacagttca ttttcttttt tgtctctgta ctctttctgc taccattctc attcttgcac 17520taatttgtgc tggtttctct ctgagccagc tgcacagctg cctgcctaag acttcctctt 17580ggcatctttt accctctctc tgtgttacat ccccggtttt ctgaatcgtg tggcgttctc 17640ctttttactt tacttcctca tttgtgttgc acgtatgctc tagttgtttt tagataaaga 17700gtgcatcaga ggtagatgtt ttgattcctt acatgcctga ctttttgttc tacttttgct 17760ctaggttaat acttgatttt gaataatatc ctaggttaga aatgattttt cgtcagaatt 17820ttaagggaat tgcttttctg ttgtctagtt tcctgtgtta ctgataggaa gtccaaaggg 17880gctcgtattt caggtccttt ttatgtgtaa cctgtttttt gttccttgag gtattcaggg 17940tctcttttta ttgctaattt ggggagcttt atcataacat gggtccttag tcattcatcc 18000tagaaaattt tcctttccta tatctttgat gatttcgtct cctctgcttt ccctcttttc 18060tcattcttaa acttctattt gtttgacatt agacctcctt gtttgatctt ctaatttaat 18120ttttctctcc tagtgtccaa tttttgaggt gggagaaaga tctcatcaat gttatctttc 18180agcctttccc ctgaatttta aaattttact cttcatattt cttctgatta atcctttaaa 18240aaaatagcat cctgggccag gtgcagtggc tcacacctgt aatcccagca ctttggaagg 18300ctgagcgggg agtggatcac ctgaggtcag gagctcaaga ccagtctggc caacatgatg 18360aaaccctgtc tctactaaaa atacaaaaac ttagccaggc gtggtggtgg gctcctgtag 18420tcccagctac ttgggaggct gagacaggag aatcaccaga acctgggagg tggaggttgt 18480agtgagctga gattgtgtgc cattgtactc caacctgggt gacagagcaa gactctatct 18540caaaaaaaaa aaaaaaaaaa aaagggccct gttccactga ggcttcagtg cggagcatgg 18600agggatacta cctccaaatt ccaaacacgt ttgacacatc taaagaacct tctaaaggat 18660gactaaacta attctgcaag ctttagcctc taacttatct ccaatttata tttaatagaa 18720ggctggaaat tgaacagaaa ggaaataaga ttatttggaa ataaaaaatt gtcagccaag 18780caaggagagc ttggcatttc tggaaacttc tttaccctgg aagaggtaaa aaagtgattc 18840tcccattccc ccaacagggc attcactaaa aattaagtga gaaatgcttt gcctagagga 18900tctgtagctt gcgaacactt gacttgtgcc actggtgtac ggaacatagc agtgtcagct 18960ctgccctggg acagtcaagg ctggctggtg ctgcctgtgg ttagagtcaa gagaggggtc 19020ttcagtgggt gcagtttgca gttccagagt ttagtagagc aaagacgtca tgaactatgt 19080gaactctgag gaaaggtgtc atagaaacac ctcaaaagga cactgtctaa gaaggctact 19140tgctggggca aggagacccc aggggtcaga ggctgtgtag ggaataatgc cagagctggg 19200gttgaaggag aatccttaga ggtgagacag aatgtgcatc attgcagtgg ggctgtgcaa 19260ggcagtggtc tccacaggag gtgaggacaa gggggagggg aggttgtgaa gaatccgtaa 19320gtgaccatga tgcaatagaa agccagaatt tgggcatttg ccataggaga gggcccccag 19380tgccagatta taatggtcac agacaaatga gatttttaac catttcctct aattcatggt 19440ccacacttaa ccccgtgggt cctggaaaca gcagctggag aatggagagg aaagtgatgt 19500gggagagaga aaactttctt tacccttttc ataactgagt ttatgaagta aactgacagt 19560agaaagataa ataggagaaa agacataaat ttattttgtg cgtacacatg ggagtcccat 19620aaaatatgag actcaaagaa aggccagatg attgaagttt atatagtatt cctgagctac 19680agaaaaggaa tcagggcttg gggcttattg aggggaggtg gtgacaggtt ataagagggt 19740gaggagagga agtgtatagc aagcataggt tgtcttgtta tgcagataaa aagtctctca 19800ggtgataaaa gttgtctcag agtcccccat cagaagaata ggtaatagcc tgtgacaagg 19860tctacctgtc caatcttctc cctggtgata aaatcttccc tggttgatga gattcttatc 19920aaagtttttt tctttataga tataaatttt gtttacaaaa agacagtttt tcagagctac 19980tcctgtgtct acagtgtctc agaataacta actggaaata catcaaataa gcatatcctg 20040atgtggcata ttctggtcat attttgggat ggtgcgtcct gagctccaat gctgaaaaaa 20100caggaacccc atttctgttg gatgtgccaa cctaaaataa tcaaaagggt cagaatctag 20160tttaaagata ctttattcaa gtgcaaagtt taaggacagt gctagggaaa cacggatccc 20220aaagaatgga agtcagcgtt ctgaacttta gaagtttggg attgtttata gagagagagt 20280ttagggaagc ttaacagaat ttcaacatct ttctgtgtaa ggcttaatgc ctagttacaa 20340tgatctgatt agtcaaggtg gtcactttca tttgagaaag gcatatttaa catttcacgg 20400gctgggagcg gtggttcatg cctgtaatct cagcactttg ggaggccgag gcgggcagat 20460catctgaggt caggagttcg aggccagcct ggccaatatg gggaaacccc ttctctacta 20520aaaatacaat acaataaaat aaaataaaat aaaaaaaatt agccgggcat ggtgcacgtg 20580cctgtaatcc cagctacttg ggaagctgag gcaggagaat tgcttgaacc tgggaggcag 20640aggttgtggt gagctgagat tgcaccattg cactccagcc tgggcaacaa gaatgaaact 20700ccatctcaaa caacaacaac aacaacaaca acaacaacaa caacaacaac aacaaacatt 20760tcacactgaa ggtgtaacag tcatgggttt gtattttcgt ttttcttggt tttttttttt 20820tttttttgag actgtctcgc tctgtattgc aggctggcat ggcacaatca cagctcgctg 20880cagcttcgat tttgtgggct caagtgatcc taccacctca gtctcccgac tagctgggac 20940cacagtcatg tgccaccaca cccggctaat ttatttttta tttcttatag agaccagatc 21000ccccttttgc ccaggctggt ctcaaactcc tggactcaaa caattctcct gcctcagcct 21060cccaaagtgc ctggattaca ggcatgggct actgtgctca tcccatgggg tcttttgtgc 21120caactggtgt gagttaggta caggacaata aaggaggcag ttaatccatt aatccataac 21180aaagatcagt gaagggggaa ggtctggtct ctggtctctc ctagtcattt acagaactag 21240aacgatgaga agagagtgaa tctataacct aagaagcaga attgcaaaca tgctatgtga 21300ctcagtttcc agtacttaac ttctcccttg gcataataaa taattttaga gagttttaag 21360aattttgttt tcttttacag atgttaacaa cctcagcttg ctgggggctg gtggtggtgg 21420ctgctcagac agtaaagcat tgaatgcaat gtgaggtcaa agttttatta cagatcatac 21480cggtctttta agtacttgca gcaagatttt cctaatactt aaaagtgact ggaaactcaa 21540taggatcagt gtgatcttct ccagataggg atggtagatt tttgaaagtg ggtgtgaagg 21600gcagtaatga gagaaaaata aaactatttc tggttgtact ctcccaagtc aaggtcattc 21660aatgaatggt tatatagatt tgcatcaaaa gtccctgttt tcagcctcac ctttggaaac 21720acctggattc tctattctga gactttctga gatgagggaa aggtggcttc tcatcagtat 21780ctccttcttt gtgcaataca gtttcagttc tttctaatct acagagttag ttccttctct 21840actgtcagct ttctaccttc caaaatgtgt taatgtcact cattatcatg tttcccattc 21900tctttccctt atggtttaaa ctttaaaaga caatggtatt tgtttaagtg aatatctaaa 21960aagatgtgga gaaagattca tgtgttcagt ctaccatgtt taattggagt cactggtaga 22020tttttaagga aaaataacat tctaggtttt tccagtattg ctatgtagct tgtctatgta 22080gatcaccttg cattcttctg tttctctctt ataacttgat ttttttcttt tcttttcttt 22140tctttttttt tcgagacaga gtctcacttt gtcacccagg ctggagtaca gtggcacaat 22200ctcgtctcat tgctgcctcc atctcctggg ttcaagtgat tctcccacct caccttccca 22260aatagccggg attacagaca tcttataact tgatttttac tcatttcatt atcatccaag 22320agatgaaatt taactcaaag caaatgacta ttgtttcaaa tacaaatctt aatcagggag 22380aaaagattat aacttatagt tgaactgggg tttggagatt atatgtgttt tttaaaatta 22440ttctgtccca catgtaacat acaagtgagg attttaaaaa tttgtctgca gttttttttt 22500ttttaattga tcattcttgg gtgtttctcg cagaggggga tttggcaggg tcataggaca 22560atagtggagg gaaggtcagc agataaacga gtgaacaaag gtctctggtt ttcctaggca 22620gaggaccctg cggccttccg cagtgtttgt gtccctgggt acttgagatt agggagtggt 22680gatgactctt aaagagcatg ctgccttcaa gcatctgttt aacaaagcac atcttgcacc 22740gcccttaatc catttaaccc tgagtggaca cagcacatgt ttcagagagc accgggttgg 22800gggtaaggtc atagatcaac agcatcccaa ggcagaagaa tttttcttag tacagaacaa 22860aatggagtct cctatgtcta cttctttcta cacagacaca gcaacaatct gatttctcta 22920tcttttcccc acatttcccc cttttctatt ccacaaaacc gccattgtca tcatggcccg 22980ttctcaatga gctgttgggt acacctccca gacggggtgg cggccgggca gaggggctcc 23040tcacttccca gaaggggtgg cctggcagag gcacccccaa cctccctccc ggacggggcg 23100gctggccagg cgggggctgc ccccaacttc ccagacgggg tggctgctgg gcggaggggc 23160tctttacttc tcagatgggg cggctgccgg gtggaggggc tcctcacttc tcagacgggg 23220cggccgggca gaggcgctcc tcacctccca gacggggcag cagggcagag gcgctcccca 23280catctcagac gatgggcggc cgggcagaga cgctcctcac ttcctagacg ggatggcagc 23340cgggaagagg cgctcctcac ttcccagact gggcagccag gcagaggggc tcctcacatc 23400ccagacgatg ggcagccagg cagagaagct cctcacttcc cagatggggt ggcggccggg 23460cagaggctgc aatctcggca ctttgggagg ccaaggcagg cggctgggag gtggaggttg 23520tagcgagccg agatcacgcc actacactcc agcttgggca acattgagca ctgagtgaac 23580gagactccgt ctgcaatccc ggcacctcgg gaggccgagg ctggcagatc actcccggtt 23640aggagctgga gaccagcccg gccaacacag cgaaaccccg tctccaccaa aaaaatacga 23700aaaccagtca ggcatggtgg cgcgcgcctg caatcacagg cactcggcag gctgaggcag 23760gacaatcagg cagggaggtt gcagtgagca gagatggcag cagtacagtc cagcttcggc 23820ttggcatcag agggagaccg tggaaagaga gggagaggga gaccgtgggg agagggagag 23880ggggaggggg agctgcaatt ttttatttag caatttccaa acctattgtg ttaggcaggg 23940ttctccaggg aaacagaacc aatagggcat atctatatct atatttatat ctttatctat 24000atctatatct ataatctttc tatctatcta tcaagagatc gagagagaga gatttatttt 24060aaggaattgg ttcatgtgat tgtgggagct ggcaagtctg aaatccatag ggcaagttgg 24120tcagctggaa attctggtaa gagttgatgt tgcagtcgtg agtctgaaat ttgcagggca 24180ggtcaggtac agtatctatt gcaattgcag tcctgaggcc aaattccttc ttcaggaaac 24240ctccgtcttt tttgctgtta aggccttcaa ctaattggat gaagccctcc cacattgagg 24300gcaatctgct ttactcaaag tctgctgatt taaatggtaa tcacatctaa aaaatacttt 24360cacagcaaca tttgaacttg tgttgtctaa gcaattgggc actatagctt agccaagcag 24420acacatgaaa ttaaccatca ctctgtagag atgaaagaac tactgtttca aaaaacaact 24480gtttttgaat ccgtcattta tcaacggatt cacccaatgg ttaacctttc tatatgcttt 24540ctctttctcc caagtactga atcatatgaa aataaattat ggttgtgata tttcctatct 24600aaatacttca tatgggacat tctcctacat agcacaccta agaagattag tattaattca 24660gagagatcat

gtcatatctg gttcatatat aattttccct agctgacctc aaaatgtgtt 24720tgttttgttt acatattact ctttatagtt atgtttcttt taatacggat caatatttgt 24780gtgtttttgc tgctattttt tttaatgaca ttgttttgaa taattcaggc tcattggcta 24840tttcacatcc tgaatttctc taattttatc tttatgatta gagccaggct ctaattcttg 24900gcaagaataa cactgaagtg aggttgtgta ctcctaattg ccctgcatca aagacacatg 24960atatgcattg gttcctgcat tagtcatgtt aagtttgatt agctggtgaa ggtggtcgcc 25020accatttctc actcttgtaa agggacattt tctcctttta aattaatatg taatttgtgg 25080cacaagactt tgagactgtg taaatatccc attctctgac aacctttctt ctgatgactt 25140tagcattaac tgatctaatt atatcattct tggcattgag tagcattctt gtgtaaagaa 25200ggggttctct ttctctccct cctctcatta taatttgtta ctgttatttt cttacaagtt 25260actaagaatt actcaaaggc agtatttttc aataaatcat tggtaattta tggtcttctc 25320actctagaaa agggaggatg ggtcagaaag ctgaggggaa aaaaagggag gaaacgagaa 25380tgtatattat cgacataatc ggttgaaaat gtctagtgct gtaattatgc catcatgcag 25440attaaaaagc cacctgtgaa aaatcaactt gtattgtttt gttttgtttg atttttaata 25500aatccttata gtgtatgaat aaaaattaaa ttaattgatc agtatcttca ctaatggcag 25560agaaggggat ggactgagca gattctgctt ttcactctga tatttgttaa ttgccctgtg 25620tggtctgaag acctgggttc tagtaccagc tctccctctg cagacaggtg tgttactttg 25680gtcaaggcaa tcaatcttct tgatactcag tttggttctc tctgatttga gcataagaaa 25740tatacttgaa ggccgggcat ggtggcttat gcctgtaatt ccagcactat gggaagccga 25800ggtgggagga tcgcttgggc tcaggagttt gagaccaggc tgggcaacat ggcaaaacct 25860caactctaca aaaaacaaac aaaaaattag ccaggcatgg tggtgcacgc ctgtagtccc 25920agctactcag gaggttgagg caggagaatc ctgggaggca gaggttgcag tgatctgaga 25980ttgtgccact gcactccagc ctgggagcct gggtgacaga gagagaccct gtctaaaata 26040tatatataca cacacttgaa tgcttcatgt cccttgctca gtgacagccc cgtcctctgc 26100ttctgcacag ttgaccaagg cttctcagtc tactcctgtg tagaaaagaa ttaaagcagg 26160cctgaggctg ctagtcttag aaaggcttgc aaagttggcc cttgtctggt gtctgggaac 26220ttgaatttct ggagggttct caccattccc tgaaaagaat ggctcacgat gcctaaaata 26280tttgtacaaa caatgaagtt tctgctgaac atctgcttcc ttctgggagt ctggaatttt 26340aggatgtgct aggtaggggt gtttacatga cagccccaca taaaaacctt gggcactgag 26400tgtctaatga gattccctag taagtaatat tttacacata ttatcacaac tcattgctgg 26460aggagttaag tgcatcctgt gtgactccac tgggagagga ctctgggaag cacatgtctg 26520atttcctttg tcccatgtgc cttttccttt tgctgatttt tgccttgtaa attttttttt 26580ttttttttga gagacagagt cttactctgt tgcccagact ggagttcagt ggccccatgt 26640cggctcactg cagcctctgc ctcctggatt caagcaattc tcctgcctca gcctcccgag 26700tagctgggac tacaggcgcg cgctgccaca ccggctaatt tttgtatttt tagtagagac 26760ggggtttcac catgttggcc aggatggtct tgatctcctg acctcgtgat ccgcctgcct 26820cggcctccca aagtgctgga attataggcc tgggccactg tgcctggcca taatttttat 26880cctgtaataa attatagtcg aaagtattga gtcctgtgaa tcaacttaga gaatcaccaa 26940actgcttcca attttctcat atgtaaaatg ggttgctata ataatgatga tatctacctt 27000atagggttgt tttaagtatg aaaaatatgg tgaaatatgt gtgaaactag gggccggatg 27060taggatgagt catacagtgg gtggttatta ttacggatca tattaactct tcaggtaaaa 27120accatcttgt agctgggcaa ggtggcacat gcctgtagtc ccagctactt gggggactga 27180ggcaggtgga tcgcttgagc ctaggagttc aaggctgtag tacgctatga tcacgtctat 27240caatagccac tggactccag cctggacaat gtaatgagag tctgtctcaa aaaaaaggaa 27300caatcttgtg tttgcgtgtg tgctcatgtc tttgttggaa taatactgac acagtcactc 27360aaattaactc tcaaatcttt gattattcat ttgatgggaa caacaggttt atgtgccagc 27420ttatcaggac ccctagttct ttcattaaag tgtgtatgtg tgtgtgtatg tgtgtatgtg 27480tgcacatgtg tgctagtttt cttatctaac gacgaagtcc tttgggaggt ttactttttc 27540attactattt ttttcatgct ttcctttgat gtgcacctgg caatttatag agccaatgtg 27600tactacatat tctgctgcag aaaatgacag aggtgaggaa ggagcaggaa gcagatttag 27660aaaggaatgt tacagtttat caagttgtga ctaatggaag ctattaaaac aaaaggtacc 27720aacccatctt aaatattcac tgcctctaca actatttttc tataactgtt gttccttgtc 27780agctctgggg tggagggaat attcctgaat gttttattaa gtaattcaaa gatcttccta 27840ggtatgtgta tcaaagatcc tatgatgtat ctgtcttgta aattgagact ggcatatatt 27900gggcttacat tactgggaaa aatgtatgtc atcatcattg gtgaaaaaga gtttccatag 27960cagttttttc taagtagaga gataaatgaa tcagactttt ggaggaggta tgttttaact 28020cactggagga tcacaccaag tctgaacatc taaggaaccc tagtggaaaa ctggttttcc 28080tgtatgctgc tctagcgatc tgaggaaagg cctaaaaaaa gccagtgtcc ctgtgatatt 28140gtgaaataca tatatgtggt ctttgttcct gtttcctggc atacaagtac taaaaatcct 28200tggaatctcc aaagtgctgt ctttttgtat attagtgttg actgatagct tcagagtggg 28260gctggtcaag ttgatcacca atggccagtg gtttaatcag tcatgcctat gtaatgaagc 28320ctccatgaaa atccaaaggg aatggactgg ggagcttcta agaagtgttt tttaccttcc 28380cgtgagcctc ctgtgctgaa cacgtggagg gtcacgggaa ggtaagcaaa aattcattca 28440catgctggga gggtggcaca tcccaactcc acgaggacaa aagctcctgt gctcagaacc 28500cttccagact tggaccttgt atctcttcat tggcttttat ttgtatttta aaaaatatcc 28560tgagtgataa actggtagat gtaagtgtct tcctcagttc tgtgaaccac gctagcaaat 28620taatcaaacc ggaagagggg gtcatggcaa ccccaacttg aaacctgttg gtcagcagtt 28680ccagagacct gaacttatga ctggttggaa ggacggggtg ctcttgtggg actgagccct 28740caacttgtgg atctgatgct atctctgggt agacagtgtt ggagctgaat tggaggacac 28800ctagcttgtg tccactgcag aactgattgc ttgcttcctg ctggggagaa atccctatat 28860attttggggt ccagaagtct tccgtgttga ttgtttttgt gtgagagcag aggaaaaatg 28920gtttgagagt ttttcgggaa acagcccctc ttagtatagt ggtagaaaca ctccaaaaat 28980aaaatatgct accccaaaaa taaaaaatga aaataaaaat aaaaatctgg agtggtcagt 29040ttgccaagag gatttatgga gcatctaagg tcaagcatta cttctcagcc ctgcagcagg 29100cctctaatta agccatgcca cagagtgcgg tttgcagaga ggtggagttc ctgtggattc 29160attcttctct ctaaaattat aaataacgca gcttccaaac atgccatatt acctcacaag 29220gtctaaagac tcaatatgaa tcttcaactt aacaattata actgacacag attgagatct 29280tcctggatgc tgaaataggc tttacatgat ttatctcatt tagttctcat aaaactctat 29340tattaatatt attttacaga tagagaaatg gaagcacaga gagggtaagt gtattagtcc 29400atttttatgc tgctaataaa gacataccca agacagggta atttatacag aaaaagaggt 29460ttaatggact cacatttcca catggctggg aggcctcaca atcatggcag aaggcaaaag 29520gcacttctta cctggtggtg gcaagacaga aaatgagaac caagcgaaag gggtttcccc 29580ttataaaacc atcaggtaac atgagacaat tattcactac cacagaaact atatggggga 29640aaccgccccc atgattcagt tatcttccat tgggtccctc ccacaacacg tggagctaca 29700attcaagatg agatttgtgt ggagacatag ctaacccata tcagtaagta attagacaaa 29760ccttgcaaag ctagtaagtg gtattgctgg aattaaatct gccaatgtca ctccagagtc 29820tatgtgattt actggtatat tatagggtct acctataagc ttgataacct tatgttagaa 29880caaataacca tgacatattc tgttcagtag tttgcatttc cttttgactc ctacagggga 29940ggaggccgag gttcagggac attaaagtgg ggtttagaga cattaggtgg tttacccaag 30000ctttatctac tagatactag ataattgtct atctgacaat aaagctagaa cttacaccca 30060gctggacaat ggagctacag cttaaaacaa aatcttctaa tgagctcaga actcatggct 30120taataagatt tgggaaaagt cctgcggaca tttcactgtc tatccagaaa tgcgaggaag 30180ttaggagaaa aggcaaagta tctcatagac agataaaggc agttcagtaa gtagcctgaa 30240taaatagcca tatttaaaat ctaatttggt tcttttgtgc ctaacacaat tgactttatg 30300ctggtatcta ttttctgctc tgtctctctt tctgtctcta cttatgtgtg tatgcatgtg 30360ttataaaata tatcagccca ttgatcaatt tttaatttaa gcaaaaacat ggtagattaa 30420tatattcaat caatttattg agtagatatt tatcgaggct cacacattta tctgactgtg 30480tactaagcac tggaaaccca aagagaatga agtcactgcc tagacagttg gaggctgaca 30540cataaacaag cagggtaata atcaagtgtc ataactagtc tattacatgc aatgttaaac 30600tagcatctct accatgcaaa acttgtgctc ttggggatac aggaagactt tccagagaag 30660tacacaggac aggaatgtgt taggaaacca gtcagttccc aggtcctcga tcaggtcaca 30720gtgacttgcg attctatttt gaacataggt cttaaatctt tattttgata gcaagggttt 30780taaacttttg atatatgata tacttctgaa aatcaaattt catattctaa aattaagtat 30840ttttgccctt aactaacttg aacataatac tataatacat taacatatat tattaataat 30900aaataggacc cctggaagtc caagagagac atgaggctta tttggtatgt taaaatcata 30960caggaagtgt tgttaaataa gaaatggtgt tacactttct ttgagttata tttatatgga 31020tatgttgtta atatgtgttc caacattgta tgagattcct aaaaatctga tatggacatc 31080cagtgtggtt gttgggtcct ctatgagcct agggagcact ggccggttac cttgcatcca 31140ttcatgtcag cgttggtagt gtcaggcacc cgatggttct tagaagagta cttagctcta 31200ctctgcagtg tctgaagttg ctggatatat acctgctgta taaactgctg actagggcgc 31260tgcagtttac ttactgtctt ctcatgggga ccttcccctt caactctttc ctcttgggtt 31320tcacatcttg ggtggggagt ttcatcctag tagtttgcct gagaatacag gtgaacccac 31380agaacaaagt ggacttcgaa agcatctcct tggagtgaga ctttgcttct ttctctttgc 31440tagcaccatc ttgtacctta tcgtcatgaa ctttgttggc tgaatcattc ccatttactt 31500aattgaagag taagagactg gaacaatgct cactttgatt ttcctggata agagttaaga 31560gttcttgaga tggcagcttg tttgacacat gaattttctt caaatttgtg cttactacca 31620actgatttgg tgtggaggag agcccagaga agttccctct ctctgtcaga acaactttgt 31680aacatttatt aacctgactt ctgccttcaa ttaactgtaa ccttttgcct tccaaattaa 31740aaagttccac attactccaa aaataaaaag tgaaaataaa aataaaaggc tgatatgtca 31800tggtatatgc agtaaattgc tttattctga tttttttttc taaaagcctt ttgcaaatcc 31860tgaagtgctg tgtattcaag gaaattcatg aaagggacct tgacaagtag tcttaaatac 31920aggtttctga taactttgga gatcacacct ttggactagg taaaaacatc caaaactcgt 31980ctgggcgcag tggctcacgc ctgtaatccc agcactttgg gaggccaagg caggcggatc 32040acgaggtcag gagatcgaga ccatcctggc taacacggtg aaaccccatc tctactaaaa 32100acacaaaaac aaaattagcc gggcgtggtg gcgggcgcct gtagttccag ctacccggca 32160ggctgaggcg gaagaatggc gcgaagcggc aagacggagc ttgcagtgag ccgagatcgc 32220gccactgcac tccagcctca aaaaaaaaaa aaaaaaaaaa aaaagtccaa agctctaatg 32280aaaaactgat gcattcatgc agattgctaa cccaacatca aggagaacga gaattacatg 32340ggactgagtg aatgaaggat tgaaattact attttaaagg gtttttgttt gaaacattac 32400tgattttttt tatgttttgt tttccagact caagaaaata ttttttttct tttgagctat 32460ttatagctta cagcattggg gtaaagtata cttctgtgag caaaatggaa acatttacct 32520ttctttctac ctgaattctt cagaatttgg aaactattca ttagtgttct tattttctgg 32580caatatagtt atttgcataa gttcaataag aacctatttt cggctgtgca tggtggctca 32640tgcctgtaat cccagcacct tgggagggcg aggccggtgg atcacaaggt caggagtttg 32700agaacagcct ggccaagatg gtgaaacccc gtctctacta aaactacaaa gattaaccag 32760gcgcggtggc aggcgcctgt aatcccagct actcgggagg ctgaggcagg agaatagctt 32820gaaccttggg tggcagaggt tgcagtgagc cgagatcgca ccactgcgct ccagcctagg 32880ggacaagagc gagactctat ctcaaaacaa acaaacaaaa aaacaaaaag caaacaaaca 32940aaaaaagagc ttattttctt ttgtaactgg acacatggaa acagtggtta ttttaccaag 33000gctttgactg gaatgtcttt tttttgagtg caaccggact gcttcgaggg attgaggttg 33060actttataca gccagtagac ttggaaaaag acacacctgg taccttgccc acacaattcc 33120tttatagcgt ttctaacttt gcaataagta aagaatgtca ctttctgaca ggcccaggga 33180cctcaagata ttttggagac gttgaaaaga gagcaattca cccaattcat acaggtttta 33240caggcacagt ctgatggcga atctttggct tggcttcatt gcttcaagag tttgtttttt 33300tgacacggaa tctcactctg tcacccattc tggagtgcag tggtgagatc ttggctcact 33360gaaacctctg cttcctggat tcaagtgatt ctcctgcttc agcctcccga gtagctggga 33420ttacaggcat gtgttgctac tcccagctaa ttttttgtat ttttggtaga gatgaggttt 33480caccatgttg cccagggtgg tcttgaactc ctgacctcag gtgatccacc cacctcagcc 33540tcccaaagtg ctgggattac aggcgtgagc cactgtgccc agcccttgag aggtttcaaa 33600agtcttaatc tgagattcct tatgaaaaaa ttccaacaaa gccaacttaa gagccatccc 33660tgtagaaaat atatctattt aaatatcgtc tgttttatgc cacaatgttt gttttgcgtt 33720gcaagccgtt atctcctagg catgggtaat ccactttgag aggaaaatcc agacatcatt 33780gtgcctaatt tgctgccacc tgtgtctgtg ctggatctta ccagggttag ctttattttc 33840tttcaactgg caaaattctg ataaagcatg tagcttcacg gtagagcaaa aagtgtaact 33900taattgaaag tcatgacttt caggagtcta atgatgctaa tatattttct tctagagagg 33960tgtctttatt gtatgtaatt ccctgaagaa atgtaaagat ttatctaatt cctattgctc 34020tgacaggcgt gctcaataga agcattgaag taaaataaaa ataacctttt taatctgtgt 34080atttctcttg cccaccaaga tatttaattt ttttcttgat ctttgctttt gtttatgtga 34140agatatttat gtctatatca tttctgtata tatcacagaa aagttttcac ttgcttgaca 34200ttttattcta caatgatttt tagtttaagt ttaaagaatg gctacattca gatttatttt 34260cacaactata gtcctgctaa actgcctttg ttgaaaactc agtttttata ataaataaaa 34320aatatcaaag caaaaaaaaa agagccttca tgataaatca ccattcttac tgcactttaa 34380gcagataatc atgccagaga ctaaactgac tttgcaaata aattagtttt attattatta 34440tctttgtggg taaaagttgg gatgactgta gaagagaaaa ttatatttca gaagaaaatt 34500ataccatact tgttattaga ttctagtctt gataattgtt tttttgagtt tttgttattt 34560gcctacaatt tgggctgaat cctgaattcc ttcctgggta caagtctcca aactaatgtt 34620tcctaatttt tctaccattt ttctgtcttg gaatcaccaa gccctgcagg ctttagctag 34680acaacttgat ataaactttg gaagaaataa tgacagcaac ttaatatatg agcagtgttc 34740atgtcagctg atgtatggat tactcagaag gtttacttga acacctgatt caaactataa 34800tccagaaata tctgtaagat tgccactgca atctgaagct acttcagaga ctctaggaaa 34860attagtttat agacaactcc agatgttaat ctttgttttt cttttgtttt catggaaatg 34920ccttttatta aacatctgat tgcttgattc atagaggcct gactttggtg gaagcaacac 34980cactgcctga aatgagatat aactgttaac cgtttaattg gagcggcctg ttctcacgac 35040tgcaagacta gttcaatggc ttataaaata atccacccgc tgggcacagt agttcacacc 35100tgtaatctca gcactttggg aggctgaggt gggcaaattg cttgagctca ggagttcgag 35160accagccaga gcaacatggt gaaaccctgt ctctaccaaa aatataaaaa attagccggg 35220catagtagca tgtgcctgtg gtcccagctc ctcgggaggt ggatgtggga ggattgcctg 35280agcctgggag gcagagcttg cagtgagctg agattatgac actgcactct agcctgggca 35340atacagtgag accccatctc aaaaaaaaaa aaaaaagata atctaccaac ccaatttctc 35400aactggggaa tgttgggctc ctgctctcct gtctctgacc tttcattctc ccttgaggct 35460agccatcaag actacaaccc ctcttcccca aagtgggcca tagaaacaaa accccttttc 35520cccaaagcca accataaaac ctaaaaatag tactctaact tccaccaccc ccagcctgtc 35580tgtgtaaggc cataaagaaa ttatctgact cactttgttt gactgaaggt tataagaccc 35640ccattccaga gagggtccag caccacaccc agaaggaaga aatgcatgct cagagaggca 35700agaagggtcc agacagacag gctgtgctgg atttccctgc tcagtctatt agcattagac 35760catacctttt ttgtccaatc atatttctac gtggctctcc atactttgtt taacctaacc 35820taagggggct cagggttttg gcctgggcat tgtctgttgg ggaatagagt gagtcatccc 35880cagctcatgg gtttgcatcc agttcttgtt gtaaaaggcc caaagcctgt tggatggcaa 35940ccctgagcca tcgtggaagg ggggttccag tttcacaaat agatactcag acagccaaac 36000taccatctac ttggtgccaa cgtttgcact gtggtcaaag acttacctag cacagactga 36060acaaatcttc ccatctgtca cataaatgtc cccaagcaat gttgaagcac atgccaggat 36120cggccttgct aggtcctgct tggtagataa gcaaatggct tccttgtggt gtttttattc 36180tattttgtct cattaacact acaactttgt gttatctact tgataatctg taattgtaaa 36240tacatacagg attatgtaat ttgtgtaaat acataatgac agacttctga aaactggtat 36300tttttacttg gtgtccattt gaagctgttt taggttctgt ggcacatgaa ccaatggcat 36360ttaaaaagca tactctcctt gctcttaaaa aaacaaacaa aacaaaacaa aaactgtcca 36420ttaaaatttt tgtatttttg taaagacagg gtttcaccat aaaaatggac agtttccctt 36480atatctttgg gtcttcgttc tgtaggctct cgtgtcacat aaaattatga tcaaataaat 36540ttgtatgact tttctcctat taatctgccc cttgtcaatg attttgagca accttctgaa 36600gaaagtgatg gggaagtatt ccctttgctg ccacaaggta tatatcagat aagtcagtct 36660attttcttga acatatatca cattcatagg aaaaacactt tttccaaaag attactgtct 36720tcccaaatac ccacgttctc catttttttt tttttttttt agagatgggg tctcactgtg 36780ttgtccaggc tagtctcaag cttctggact caagcaatcc tctcacctca gcttcccaaa 36840gtgctgtgat tacagacata agccatcacg cccggcccca ttttctcctt tgggtgtatg 36900tatattgctc attgtcaggc atcaaccatt tctcttctct gagatggagt ctcactctgt 36960cacccaggct ggagtgcagt ggcgcaatct tggctcactg caagctctgc ctccctggtt 37020cacgccattc tcctgcctca gcctcccgag tagctgggac tacaggtgcc caccactacg 37080cccggctaat ttttttgtat ttcttttttg gtagagacgg ggtttcaccg tgttagacag 37140gatggtctca atctcctgac ctcgtgatcc gcccgcctcg gcctcccaaa gtgctgggat 37200tacaggtgtg agccactgcg cccagccctc ttctaatttt ttatatttat catgtattta 37260ctagaactgg tttattttcg tgagcatatg ttgtggattc tactataaat aatgcactta 37320ataatcatta ataaaactta aatcctttcc gtcttgattg tggccttttc tttttgctat 37380taatttcctc agcataggtt aacctgaact cttaaaagct atttaggtac tggtataaaa 37440caaaattttc tccaaagcaa tccagtatat aatatctgga ttttaaaaaa gcagcctcat 37500ttaattagga ttaatttctc ctttcagaag ttaagtgatt ctgtttctgt aaaacgcaaa 37560attataagct taattgtttt ccacacagga aatgaaattc ctaatctttt tatccagaat 37620cttcatgtgt ttgtctctct gtccatctgt cactcctttt taaggtacct ggagatgacc 37680tagaggcttg ccacgcttag ggtttcctcc ctgtgcagaa gaagatggga agtgcaaatg 37740aggacgaggg gtggggaggg aagagggagt caggtgattc agcaagtgca ggagcccaca 37800gactaagctc aggaatttgc actttgtctg ctcgcagagt gagtttcatc gtggtgtgta 37860tatattgaga tatgcaacag actccactgg aatgtcagaa gaacttatgt ttatttttcc 37920tctaacatgt gggaaagatt aaactgtatt tgtatttaac tcacatagat tggcacgtgc 37980tcattctgtg tgtcaccctg ccacgctgtc acaaacttcg agcagggtcc tgaggggaga 38040ggagggcata gctcctgctc ccagggggtt gcctgtgtag ccctgcgcat tcattctctt 38100ccagagggtt gtgatttgtg gcggtctgtg tgagcctggt taaggagagt tacagattat 38160gtcatctggt gttaactgat aatctttgca aaagggacat tggctttaag agatgtctgc 38220aaaaaaaact ctaaacaaac ataaataaaa atttaaaagg ataaagccag aataataatg 38280aaaatattag taatgtaaaa caaggaaatg tgtcatgttt ttcatgataa ctaatatttt 38340ttcaattttt tttttttttt aagacagtct cactctgtca ccaggctgga gtcagtagtg 38400cgatcttggc tcactgcaac ctccacctcc caggttcaca caattctcat gtctcagcct 38460cctgagtagc tgggtttaca ggcactcgcc accatgccca gctaattttt gtatttttag 38520taaagacagg gttttaccat gttggccagg ctggtctcaa actcctgacc tcaggtgatc 38580ggccgccttg gcctcccaaa gtgctgggat tacaggcgtg tgccactgtg cctggcccca 38640gttcttatta taagttctcc attaaccata tcatgagatt aaaaaaacaa caatgatttc 38700atcggaactg acaaatagtg ggtgacacaa ttttgatcat caagaagact ttaaaagaag 38760gatttgtatc actgtcatta ctgattactt ggcccttgtg tatactgggc ctttagctag 38820ggctggtaca ataaaataac catagttaga aagatatttt aaaggattac ttatttcatg 38880tttatctcac ccttttatcc ctatttttgg gcatgattta ttattattag gtttttaaat 38940aaataatgaa ataagcatgt taggtttgca tgctgctttg gttaacattg ctatataacc 39000aaccacccca aactttgtgg ccttaaaaca ataatttatt tatttattta tttatttatt 39060tatttattta tttatttatt tttgagacag agtctcgcta tgtcacccag gctggagtgc 39120agcggcatga tctcggctca ctgcaacctc cacctcctgg gttcaagtga tcctcctgcc 39180tcagcctccc gtagagctgg gattacaggc acccgccatc aagcccagct aatttttcct 39240ttatttttag tagagacggg gtttcaccat gttggccagg ttggtctcga actcctgatc 39300tcaggtgata tgcctgcttt ggcctcccaa agtgctggga ttacaggtgt gagccactgt 39360gcatggccaa caataattta tttttatctc tcatggtctc tagattgcct gggcccggct 39420gagcagtctg agtcagcctt atggtctctc atgtgttttt aatcagtcat gaggggccgg 39480catcatctga aggcttgact gggctggatg tttaagacag ccactcacag ggctgacagt 39540gatgctggat gttgcactgt tgactaatga gcctgcacgt ggctcctcca tgtgatttgg 39600gctatttata gctggggtga ctgggttcta ggtggggtag ttccaagatc cttccaagag 39660gaagaaagca gaaactgcct ggccagttag tgtatatgct tagtcttaga acagtgtcac 39720ttccatattt

ctccatagtc cattaatcaa agcagttaca ggaagcagac agacaggaag 39780ggaaaacaca atgcaacaga aggagagatt gaagtgttgg cagctgcaag ccaagaaaca 39840cctgggttac cagaagctag aagaagaaag gtaggattct cccctacagg ttccaaagga 39900agctgggcct gtccacacct cacctctgga actatgagac aatcactttc tgtgggttta 39960agctacccag tttgtggcac tttgttacta ccgtcctagg caaatgatac agtaactaca 40020tacacagtac atagaattgc tcattttact tcgttgaatg ggacttggca ttgaataagc 40080ccaaatgaga attcttttgt caagattttt ttatggctca cttttccaga gacgtgacat 40140ggcaggagta aggggagggt ttggcaggta ggaattatac tcatctgtca ttgtcttccc 40200aataccaacc aggaagcatg taaataatag ctgtgcagtt tgttttctga accaaactgg 40260gccttatttt ttttaaagaa actttattaa acaaacaaaa acctagaaac actagatgta 40320tatttttaag gtttctctca cataatatcc taatcatcag tataccgtaa tccaagggct 40380acatataact gaaaaataaa tgggtcttaa aaaaattaaa acatggtata taacactagc 40440taacatgtac tgagcagtta ctaagtgcta agtactgcta agtcctttat agatatcttc 40500atgttgagtg tcgtcactgc ccattactta ctctgagttt aaatatgaga ctcaaaagag 40560gttagtaatt tgccaaaagt catagggctt ataagtgata gaaccaggat aacgaatctc 40620aaccaaggga cttcaatgcc caaaccggtg ctcagactgt agccccatgt agttagctat 40680ttacatttga aaaaattttt aatgtttatt atttttttta agacagggtc ttgctctgtc 40740acctaggctg gagtggagtg gtgtgatctt ggctcactgc aacctccacc tcctgggctc 40800aagtgatcct ctcatctcag cctcccaagt agctgggacc acaggtgtat ggcaccacgc 40860ccaactaatt tgttgtgttc ttggtagagg tgagtttcac catgttgccc aggctggtct 40920tgaactcctg agctcaagtg acctgcccac ttgcctcacc ctcctaaagt ggggggatta 40980caggtgtgag ccaccatgcc cggcccagct atttacattt aaatataaat taaaatgaaa 41040caagattaaa aattcggttt ctcaatcaca ctaaccacac ttgaagtgct cagtagctac 41100atgtggctta gtggctacct ggcagatata gaacgtttcc atcagcacag aaagttctac 41160tggaaagcat tgatccaatc tctttgaaca gtcacaatgc atataaagtc cttattatga 41220ctgtacaagg gaagacaacg agtagaggaa ggcagaaaat aggaaaaaag gaagaagaaa 41280gatttagggt gagggagagc agttctatga agaaaagaag ctcatatcta ggagtggagt 41340ggaccctgag aacatgttag tctattatat tctaaacttt ggcagttaaa attccaaagt 41400atattaagta catgctttct aaaatattag agagctgcag ttcaacagat ttttaactct 41460ccacagcatg tccggcactg ggtgaggtgg gatggctagg tgaataatat aggcattgtc 41520atgtgtgttc gtgtgaagag accaccaaac aggctttgtg tgagcaataa agctttttaa 41580tcacctgggt acaggcgggc cgagtctgaa aagagagtca gcaaagggtg gtgggattat 41640aattagttct tagaggtttg ggataggcgg tggagtagga acaatttttt gtgggcaggg 41700gatggatctt acaaagtaca ttctcaaggg cgaggagaat attacaaagt accttaaggg 41760cagggaagga tattacaaag taccttctca agggtgggga gggtgtatca tacaaagtgc 41820attcacaagg gtggggaaat atcacaaagt acattatcgc aagggcaggg agggtgtatt 41880gtcacaaagt caattgatcg gttagggtgg ggcaggaaca aatcacaaca gtggaatgtc 41940atcagttaag gcaggaacct gctattttca cttttgttga tcttcagttg cttcaggcca 42000tctggatgta tacgtgcagg tcacagggga tatgatggat tagcttgggc tcagaggcct 42060gacagacatg aacttcccat cataaaatta gaagagcatt aatcaaatga ttagaataaa 42120atattaccat tattttgaaa tggcaagcat tgtatgtaaa taaacagcag aggaacccac 42180tgtagcctag acagggttca gagacgttcc tgccaaggac atggcacagg gactgaacaa 42240ggaaggatga cagtgcctgg caaaggcagg gaatgttaca ggtatttggg cacctgtgag 42300aaggcctgat gtccgaaagg actgaaataa attaaatgtg tggggggaga gagaaagaaa 42360gagcctagca aaaggtgagc tggagagtca gaggcagaag gcagaatctg ggatgggctg 42420ggagcttgcc aatcattttg tcaaatgggt gatgtgaagc cttgaaggtt ttttgaccaa 42480gaggagatgt cttcagattt gcgtttgaga cattttcact ggttgtcatg ctaagaatgg 42540cttaaagaga agcaaggctg gggtcagagg agctgcttgg aagctgtttg gtactaggat 42600gcggataaca tggttggaga aatggcaact gtcagggtat ttggagcaag aatggataga 42660cattggtgat catcacttgg atgcatttga gggacaactg ctatgtttct actagagcaa 42720ctacatagag caggagtaag caacttacag tccacagacc acatttgctc tgtcccgttt 42780ttcaaataca gtttaatgga aacagagcca tgcccgttct ttcacctatt ctgcatggct 42840gacatcaggc atggttctaa gtaatataca taagtttcat atattaatgc tcatctatcc 42900cagttgacaa acatgaagtg ttgctattgt ctcattttac agcggagaaa actgacatag 42960agattctctt tcgcacccat agcttcagtt accacctcta tgccaatgat tcaataatac 43020ctctaatcca gacctcttct ctgagcttca gacaggcaga tctctcacag ccagtcttgg 43080agacacttca gaaatcatag gtcccaaacc agactcctcc tcatcccctc aaacacattc 43140tttttcaaca ttcctttttt cttagtgaac atcaccaaat agataagcaa gtcagatcca 43200aggaggcctc cttggcactt ctctcatcct tgtcccacct tatatcatct atttttcttt 43260ttcttttttt ttgagatggt gtctcactgt gtcacccagg caagtgcagt ggtgtgatcc 43320tggcccactg cagcctcaac ctcaccaagt tcaggtaatc ctctcacctt aatcccgtga 43380gtagctggga ctacaggcac atgccaccga gcccggctaa tttttgtatt tttaccagag 43440acagggtttt gccatgttgc ccaggctgcc accttatctc cattcttgct gaaatctggc 43500tgtttctctc cacttctatt accaaccacc agccaaatct gacttattaa aaggatcatc 43560tcgtatgtgg gttctgtaat agcttcttca aaatccattc ctctccaccc agaccctctt 43620ccaatctcca aactgcagcc aataccttca attctgtcac cgctcctgca tactccacct 43680aatccttaac ctttcaatgg tttctcttgc ccctaggtta agctaaattg aaaactgcta 43740aagctacagc ttcttagtgt aactagtaag tacagtgact actatgtctg gtttacttca 43800gctgttgctg actaatagca cttcttgaat gaagaaatta tattaccgta ctgtagggaa 43860aaatttgtac ttcaatggaa aactgaatta tttagagcaa acctttaagg ttatctgatt 43920ctgattccat gggccctttc attgggtctt acattgtttc attgtttttg agttatttta 43980cagatgactg atagaaatgc aaaataatta ttgcatgcag tcatgcaagt aaaatctgaa 44040ggtcagggtt caattaactt ctctccccta ctgtggaaga agccaatttc atttgcatat 44100tcatttcaat atttctgacc tataaacatg cctgttcttt gaaccagttt ttatatctgc 44160ctggtaactt cattaaatga tttaaataaa ctctataatt tagtttattt tatacctgta 44220tgacagtcag gcttttacct tatttttgct ttttaaaatt attctttagc tctccctaag 44280gcactacttg gctggccctt tggctactca ctagcccaag ctccatcctc ttctgtctac 44340cgcagcccca ggctctcttt tggccctttg ttccagccct cctcagagaa gttcttttgt 44400cctggaactc actttcatac caggtgctct tcatcccttc ttcctttagt aaatttcttt 44460aatctttcag atttctgctc aaggatcact tgctgaaagc ctttccaggc ctttctgagt 44520caatacaatc cattattaga ggctcttaga gcacaggcag cacttgttat aattttacat 44580ctgtctgtgg gattccttaa cactttctaa cacaattaac acttttctct ctggctgggg 44640gcaatgcatg ataacaggat gatggtatgc tctcaaccct cccccagcaa ctagcccagt 44700gcttcgaaca tggtggatag atacaccgtt tttattttag acagattttt gagtagcaag 44760tacctactgc tcaggagaca gatggactga aaaaatatat ttgggagtca tcagcacata 44820ggtgcagcca tgaaaatgca cgagaagcaa aaccattggc aggaacaaaa tgaaggctat 44880tagagacctt atttaggtgg aataattgga cagaagccct taatggggag gaaatagaag 44940cagttaatac agatggaggc cgggcgccgt ggctcacgcc tgtaatccta gcactttggg 45000aggctgagat aggtgggtgg cttgagtcca ggagtttgag agcagcctgg gcaacatagc 45060aaaacccggt ctctacaaaa aatacaaaaa ttagcccggc gtggtggcgc aggcctgtag 45120tcccggctac tggggaggct gagatgggag aattgcttga accggggagg cggatgttgc 45180aattagacga gatcgcgcca ctgcactcca gcctgggcga cagagcgaga ctccgtctca 45240aaacaacaag gacaaaactt atcttataag cgaccctgga cttccaggga cactcgccgc 45300tctatggtgg tacgtgacct gcctggactc tgtggtcttt ggagcttggg accccacccc 45360agcgtaagag gcctttctgt gccttgtata aaggagagga aaagtgtagg ttttctgagt 45420tgataagatt agagctacag tatattatca gtagcgttgt atgaaaccat ttaaaaaacc 45480aaaccggatt taaccgcttt cacccagaat aaactgccct ccccctcttt ccaagatcaa 45540gtcagcccca gttaccactt cctattaatt taaaaaccag gaaggctcat aatttaggct 45600gacgttgccc caggcgaaca ctgcatataa gacaatagct attccaatcc tcctttccct 45660ttctaaaccg aatagtactt ctaacatcac ttttccagtc ctctttctaa atattgcgat 45720cacgagccta catcggaaaa ctatgaaaac agtatgattg gagctcttga tggtctgctt 45780tgcctgaaaa cgatgaaagg cattgagatc tttgggcaga aatggccctt agggaatgcg 45840agcctggtag ccccataaca ccccgagtta caaattcggt ttgggtaggt ggcgcaggga 45900aatctaaaag ctggattcac gttctccccc ttcagtttgc acatagcggt cagtggcaga 45960caagagcaga cgcacaaatg tcaatccccg cccgcaaact ctcgagggca gaaactgctt 46020tttgtcagtt ggatttggag tcggtggaaa agctgcccta atgtagtttc tccgaggttt 46080ccttagcctt gaccgagggg cgcttcccgg ccattcacct agaggttgtt taataaacaa 46140ggatgctcgc gaaatatctg cgcttggaaa ggcgctcgtt cgtggcgcgc attctcgggc 46200ctccgcaagc gaccccggtg acagggacaa ccgcttcggt tttagcgact gcagacagac 46260tgggacgaga cggttggagg ctcctcccca agggatgctg gaggggttgc gtcgtaccct 46320gcgcctggcc ctggcgcgcg gccccaggtc gtggtaccca gcgccctatg ggccgtgcgc 46380cggggcttgg ccacaccgcc tgctttcgct tccagccgcg cgctccgtgc cactgccgct 46440ctctgcagcc ccgcgtcccc gcagcctccc catggccagc ccgcttcgct ccgctgcggc 46500ccttgcccgc caggtacctc gaacccgggc gtttgcggaa ggggggagga ttggaacccg 46560ggtctcggta gctcgcgggc ctggccgggc gccttgtcgc cgtttcctgc accatcctcc 46620ttcgccttgc cctccattcc gcctccagcg aggcgtcttc ccttccccgc atccctgccc 46680gaaatctgga gtcccagcct gcaatctcca cctcttcgag gttcccgctg cccaggtcta 46740gcaccctcat gggtaacccg ctccggagcg tggcgaggac cgccacgggg gacgtgaggg 46800tagctatgga ctcgctctga gggaggaggc gggagctgaa tctctgggct gccagaaccc 46860acagccacat cctacgtgac tctgccaccc caaaatattt tgaccgcagc cttctgcctc 46920cttggatctc ttccttcccc acccccaccc ccgtagttat ttagcagatt acgcattaaa 46980acaaatgtct gcaggttttc ccaattagtc ccgcttccct gtgtctttat cttttaaatt 47040gcccactaat accatgaggt ttaaggtgtg gggtggatgc tgcggcatcg gaggaccctg 47100ctggtggagg aaatggttca cgcccgtccc cgttcccttt gcaggcttgc tattgtgcgt 47160ctgtgattga caagaccacg aggctgagcg cgccctggag atttttctat aaatggctta 47220acaccccagt ctagactatt tgctcggata taagggagac aattgttttt ttgttctttg 47280ccggcgaacc ctggctctgt agggctgacc tggaatttaa ccagtcttcc ctgagccggc 47340ggaggaggac aaaaaccgcc gcgaccccgg cagggtggga agtgcagggc agcgctccca 47400agacacgctt gttggaggtt cgggcctggg tgcttggttg tctgagcctc cttttttgtg 47460tttgcctggg tcctggagag gagcgcacgg tatcatggtg agcgtcacgt aggttacccc 47520gggtcccgct tacccacctg catttactta atggtggttt aattcttctt taaggattgc 47580agtaacggat gctccgcaga gtgtaccgga gaaggaggat caaaagaggt ggtggggact 47640tttaaggtaa gttgcttgcc agaggcttag tgtctaaagc aacgttcaac tgaataaatc 47700catttcttgt tgagattcgg ggaaattttc actgtgtggg ttacccagtt cctaggttgt 47760gttgccagac ttttaaaatt ccactcttag aggaaaaaaa gccatttaga gagtgacagt 47820acattcatca caacaaaaat tatctagcag ctaattgctg attttatttt gagtcatata 47880tttttcttga aaaatagtca atgcgtaaat attaaactag ttgtttatca gattccataa 47940tacgtacaaa ccttcagtct acttgtagaa aaagttaaac tgtgattttt ctctttcagt 48000agcacataac actctacagt gaaagtgttg cattttcttc ttttctatct gaattgcggg 48060gtttatatag taaatagctc atacttcaaa cagtgagaaa caaagcacgt tgaaaactgt 48120acaaatacaa atgtaagatg taatattatt ttttctataa gtctatctcc taccctccct 48180cctcgtggag gttttagctt cttcttttta tgcctagtgc tgctcttctg cctgtttgag 48240tcactgtcaa ttgtcatcag acaattgaca cagagtgtcc taatgatctc acatcctggc 48300ggttcagaga gggaaggaaa cttgactcat cagtttctca cacattgagc tctctcacag 48360tgtgctggag actgtgccat gcattggaca tccaaaggtg aattcaagat taggtctcta 48420cttgcaagga atttttattt tatttttctt tttccttctc ttgctgtcat cttagcaagg 48480attttttaaa aagcaaaatt agaatattgc aatttctttt ctgttttttg agacagggtc 48540tcgctctgtc acccaggctg gagtgcagtg gcacgatctc agctcactgc aatctctgcc 48600tcccaggttc aagtgattct cctgcctcag cctcctgagt agctgagatt acaggcatgt 48660gccatcacgc ccagctaatt ttgtattttt agtagagatg gggttatcac catgttagcc 48720aggctggtct cgaactcctg gcctcatgca atccacctcc caaagtgctg ggattgcagg 48780cgtgagccac caagcctagc ctgaagaatt ctttgcaaag aaaaatatca actcaaattt 48840aaataatctt ttcctttctt tttctttttt ttgagacaga gtcttgttct gttgcccaga 48900ctgaagtgca gtggcaccat caattaggta tcactttcag ccttgatctc tcagactcaa 48960gtgatcctct tagcctctca agtacctgag actatcggct tgcatgccat caggcccaac 49020taatttcgtc attttttgta gagatgggat ctccctgtgt tgcccagact gatctccaac 49080tcctgggctt gtgcaaccct cccacctcgg cctcccaaaa tgctgggtca caggcataag 49140ccacaatgcc tggccataaa taatcttttt tatttgttaa tttagatttc tgtatattag 49200gttttattta ggggaattgc ctgtttacac tcatgtattt acacatcaaa acatgagtta 49260tggtggatgt attcacagca catatgtaat aaggcatgtg taaaaatgat attgataatt 49320tagggaataa aaatggtaga ttttatagac catctttgtt tttgatatac ttttctctgt 49380ctcaaaaaac aaaaacaaaa acaaacaaac aaacaaaata tatatatata gcctacattg 49440ttgttaacta taatcaccct actctgctat gaacagtaga ctttatcgct tctatctaac 49500tgtatgtttg tactcattaa ccaacctctc ttcctccacc tacacccttc ccaccccctg 49560ccatcttctg atatctatca ttctatgagt actctcttcc tccatgagat caactttttt 49620ttttagctct cacgtatgag tgagaacatg caatatttgt ttttctgggt tttttttttt 49680ttctgtgttt ggcttatttc gcttaccata atgacttcca gttccatcca tgttgctaca 49740aatgacacga ttttactctt ttttaatggc tgagtagtat tccattgtgt atatgcacca 49800cattttattt gttcattgat ggacacttag gtgattccat gtcttgacta ttgtgaatag 49860tgctgtaata aacatgggac tgcagatatc cctttgatat actgatttcc tttcctttgg 49920aaaataccca gtagtaggat tgttggttta tatggtcatt ctacttttag tttttttttt 49980ggaaagcttc ataccatttt ccacagtaga taaactaatt tacattctta ccaacagtgt 50040ataagcgttc tcttttctct gtatcctcat cagcatctgt tattttttgt ctttctaata 50100ataaccattc taactgtggt tgcttttgac atatttctct acctttttgt taatctacat 50160catttataac atttcatatg gccttttggg tctctcttgg gtagttttcg tatttcttct 50220cccctcccca tttatgatgc agtcatatta catgaggatg cagttttgca gcagggccta 50280gcaatgagat acgttgttac acatcctggc gaatctttct gtggactcta ggatcctctt 50340catttgcaag aggtcagcca tctatttctt ccaattcctc cagcttcaca tatctccaca 50400gaatgcaaca ctgcaaatct gcagttctct tcatgatcct ctttattaga ttttaaaaga 50460gtatctccaa aagatgaaca tagtgcctaa ggctttccaa atggagtaag aataatgcac 50520aagaacctag aataaagtta ttaaatgtct gatacagttg taatacagac ttgatttttg 50580aaaaatgtgg ccaatgaaga gaagagcaaa tgtgctatac gatggtgagc aaaaggtgtt 50640gacaggcctg gcatggtgac tcacccctgt aatcccagca ctttgggagg ctgaggtggg 50700tggatcattt gaggtcagga gtttgagact agcctggcca acatggtgaa accctgtttg 50760tattaaaaat acaaaaatta gccaggtgcg atgacacatg cctgtaatcc cagctacctg 50820ggaggctgag gcttgagact tgcttgaacc ggggaggcgg aggttgcagc gagccgagat 50880tgtgccactg cactccagcc tgggcaacag agcaaaaaaa aaaaaaaaaa aaaaaaaaag 50940tgttgactga accctggctg aaacagtttt caggtgcttt caacaaattt acacttccct 51000gccctgagcc tccctatttc agaacaaatg attacccaac tgcaaacttt gaattaggaa 51060gttgttttta atatgccctg tttttctcaa tatttcttgc catttcacaa tcagttattg 51120tggcattcca attcttccac aaacatatga tgtgaaacat cctgacttcg atgtcatcag 51180ggaatgtgga gcattggaaa gagacagatt aattatgcag aagaaagtat catttgacaa 51240aatattattt ttatttatct ttggaaagga aatctagaaa aagaaaatac tttttaaaga 51300acactgataa aaattgttta taaaatttgt ttcctttagg aaacaaatcg ttcccttaaa 51360actacatttc atatctgccc caaacgagtc acatgtcttc agctaatatt gcttgtttac 51420gtttgaactt tattcaattc tatcacctag taatttagta ttcttaggta atttctcttt 51480gagctcaggt taaaagttgt tatttttagt tttcagagtt gcagaatttt tttttcaagt 51540agagaaaagt tcatgatgag attctgaagc cacctaatcg tatattactt tgaaaaactg 51600gatatatgcc gggcgcggta gctcacacct gtaatcccag cactttcaga ggccgaggtg 51660ggtgggtcac ctgaggtcag gagttcgaga ccagcctggt caacatggtg aaaccccatc 51720tctaccaaaa atacaaaact tagccgggtg ttgtggcaca tgcctgtagt cccagctact 51780caggaggctg aagcaggaga atcacttgaa cctgggaggc ggaggttgca gtgagcccag 51840atcacatcac tgctcttccg cctgggtgac agagtgagac tccatctaaa agaaaaagca 51900aaacaaaaca aaactggata cagggcagtg cttaggtaca aatcagaaag ttagaggttg 51960ctattcatat cattaagaaa taatgtgtct tacgaaagaa tgtagcagtt tactgaaata 52020gaagtcatac ctagaaatgt aataatttat ctttaattgt cagaaattta actgatatta 52080tgaagttcta attataagaa cacttatttg aggttaaaaa ttaccttatt ctatccctgc 52140tttgccgcta atttgatctc tctggattag tgggttattg tgggtcctat gggtatttta 52200aggagaggtc tcagaaaact aaaaattata tatactggat cataatcatt cttgtcaccc 52260actctcatct ttctgttttt gttttgtgtt ttactaccct tcccctttta ctaagtagtc 52320ttagtagaag aaaatttgca ttaagtttgt cgtactgtat tgatatggct ccaaatgttt 52380cttagcccag ggtcctcccc attcactgat aaaagctaac taaggtaaat cacaggtgtt 52440tattgtgcaa gaatactgtg aaactattca tgtaataaaa agtttgtgtt agaatttcac 52500tctctttaaa tcctggacat cttctgtgag tgtatctgaa agcagccaga catcttcagt 52560atttaagaaa ccctttacta ttctgtgtgc taggcactgt gttagctttg gaattcaact 52620gtgaatactc tagccagact tcttgtctaa atagtccaga ataggggttg ctaaactttc 52680tttctttttt tttgagatgg agttccactc ttattgccca ggctggagtg cactggtgtg 52740tctctgctga ctgcaacctc tgcctcccag gttcaagcag ttctcctgcc tcagcctccc 52800aagtagctgg gattacaggc gcccaccact acactcagtt aatttttgta tttttagtag 52860agacagggtt gtgctgtttg ccaggttgat ctcaaactcc tgacctttgg tgatccaccc 52920gcctcggcct cccaaagtgt tgggattcag ggtgtgccac tgtgcccggc ctgctaaact 52980ttcttaaatg gctagatgat aaatatttta ggcttgaggg ccatcaggtt tctgttacaa 53040ctagttggct gtgctgccac tgaagataca agaatggcgt gactatgttc caataacatt 53100ttaatttcaa aacaggccag ctggctgcat ttggtctgca agtaaagtct gcctgacccc 53160ctacctagtc cagaggacaa cgggagagaa aagggattca aagataaaaa taatttagct 53220ggaatatatt tctttaaata aacttattat acttagtaaa aagtcttaaa ttaacgtttt 53280tacttgaatt aaatagtggt aaaacaggct gggcacagtg gctcatgcct gtaatcttag 53340aactttggga ggtcgaggca ggcagattgc ttaagcccag gagttcgaga ccagcctggg 53400caacatagtg agtccctatc tctaaaaaaa atacaaaata ataataataa tggtagaaca 53460aagtcaattt tttattgaaa cttggcattt tattggcata ttacaaagta gcattactag 53520actagcctga acattacagt aatattctgt ccttaatgcc ttttgtgtca ctgtaatatg 53580agctttctgt ttgttttgga atatgttttc agcctgaata ttattctaaa aatacaattt 53640actatcattc ataatatatc aaatgactca cgtagctgca aggcagtgaa ttaaacagaa 53700ttagatcatt ttaaaaataa tgataagagc tgatgatgta aagtgaaggt ctgtatttaa 53760tttgggaggg aaaagacttt ttttgtatat tcaaagagat ggagtttgac atcccttcac 53820aacctgttac aggttgaact tgcccctgtt tttttaactg atcaaaaagt tccttctctt 53880gtgtttcttt ttttcttctc ttttctcttc ttttcttttc tttttttttt ttctgagaca 53940gagtcttgct ctgtctccca ggctggagtg cagtggtgcg atcttgactc tctgcaacct 54000ccgcctcccg ggttcaagtg attttcctgc ctcagcctcc tgagtagctg cgactacagg 54060tgcatgccac cacgcctggc taatttttag tatttttagt agagacgggg tttcaccatg 54120ttagctagga tggtctcaat ctccaaacct tgtgatctgc atgcctcggc ttcccaaagt 54180gctggtctcc tgtgtttttg tcagcattcc acagatgcta taaagttagt ggtggtatcg 54240catgcaattt gtacgcttaa tgtttggcca tttgcagtgg gcaaactggc tatgtcggga 54300gctggtgaga tgctgcttgt ggggagttgt ttcctattac tctgatttat ctttgtttaa 54360ataagagttc ctttgttcac tgtttcctcc acacagaaca gaggatttat atcttagtgt 54420tcattctcaa ctttcctgtt ttcaaagagg aaaacatttg cttcactttg ctcatttctt 54480ctccagtgca cccagaggat tttgaaggct tatgccaaca attctttggg gcagttggag 54540tgtaaccatt gctaaatagc agttcagtac ttaatgacat tcattttagt ttaacaaatc 54600attgtgagtg ttgccatttt ttattaggga aaacatctct ttcatctttc ccaaatactc 54660aacatgagtc ctatggtgag agtgaaaaag ggttgtattc tttttttgca tcatcttacc 54720ccatctgcta ttttgtccct cttctatata tcactgaaat ttggttctga tattctatta 54780ggcagtgtac

attgcagaga ttatgaataa ctggccgaat tctgaatgca ggcatgattt 54840gttcagctca gagtgttaaa tttctgtgtt agctgctaac ctttaaaagt caattgattt 54900cctttttttt tttcccctct gtataatcta gccagcgaat gctcagtagc ttttctgtaa 54960atagtgatga tttttcttcc ccaggctaaa gacctaatag tcacaccagc taccatttta 55020aaggaaaaac cagaccccaa taatctggtt tttggaactg tgttcacgga tcatatgctg 55080acggtggagt ggtcctcaga gtttggatgg gagaaacctc atatcaagcc tcttcagaac 55140ctgtcattgc accctggctc atcagctttg cactatgcag tggaagtaag tacatgggaa 55200ttaaagagag tgacatgctt gcacttcact gtgggtacta agtagcttct cctgctaaaa 55260tagctcttgg gcagtatggg ctttatcata tttaccagag gaagccgaaa atgtctttaa 55320aagttttcct atagacagtt ggattgaaga taaatcttag cagctaattt ttcagataat 55380cttgcatttt ctgtgacgtc aataaaaaaa ttatttaaag caaatagaaa ggacagctgg 55440tgggaaaatt ggcaattaaa aagccagcac tgttgataat ttaataagtc acctttcttc 55500ttagatcttc taataattga gaaagggtca ttgagaacaa tattatgatt tgattttaat 55560gctaactcca catttttatg accagtaata atgtctagtt atgcatgtta agggacatgt 55620aattaaatgt cctccttcag ccatgagttg aaataatttt aagcataaaa tgtttaaaga 55680attctttctc tggtcctttt cagggtgcac aattaaccag atgcacagta tacttcccat 55740tgtcttgatt ctcattgtat tttacttttg aatgatttgg acatctttcc cagaataata 55800ggggtgctgg aaataataat agtcttccta ttaagtgcta aaatatggta atagtaaaat 55860attaatagat taatgataaa ataacaactt ttgtttactg aattcctgca atacgttctg 55920tattatgttc catatatgaa tcatctcatt taattacctt aagtgagaag gcatgtgatt 55980aagcattcag gctttgaagt cagacatcct gggctcaaat tcggtctcat ttgctccata 56040ggaaccttta tgacttgagg aatttaatca tttgtgcttt aatttcttta tctataaaat 56100tggggtagtt ataatatcta tcttacagtg atctcataag tataaaataa agtaatttat 56160ctaagcatat agagtcatat ctggtgcata gcgagagccc agttgttagc aataataatt 56220aactcttgaa gcagtggtct catccattat aaaaggaggc tcagaagagt tgtttcttga 56280ctaatattac acagcagtaa gggtggagct aaggttccaa tgagaagctt ctttctgtta 56340tatagcccct acatgtatac accaaaatta ctaggatgct tttgcaatta actccttcaa 56400aattataaat tcatataatt ttggaaagat attcactgtc catatgtatc cacaaaatgt 56460tgaatttagg aatctaagtt tctgttccca gctcttcctg ttatgtcaat ttgaatgagt 56520tctttcatta tttgccacaa gccctcacca tgtcataagg tataataaag aacaggtgaa 56580atgaagtgct tttatttatt tatttttcag acagattctt gctctgtcac ccaggctgga 56640gtgcagtggc acgatcgtgg ctcactgcag cctcaaactc ctgggctcaa gcaaacctcg 56700tacctcagcc tcctgagtag ctgggaccac agacacatgt caccatgtct ggctaatttt 56760tacatatttt gttgagactg ggttttgcca tgttgcccag gctggtctca aactcctggg 56820ctcaagcaat cctcttgcct tggcttcttc aagtgctggg atgacagcca tgagccactg 56880ctcctggcta tgtgctttta aatttgaaag gaataatatg cccaagccca ggtcactggt 56940tctcaaactt aatgtgcatc agaatcagct ggctacatct ccagagtttc tcatttctaa 57000caagtgtcca gatcatgtta attttgtcgc tccagggacc acattttggg aattgctggc 57060ctatgggaag taaatgagaa atgatttaat gtcatttttg gaagttaaaa aagattttgg 57120tggtcactgg tttttgaaaa ctctttgaag gctgggtggg gtggttcaca tctgtaattt 57180cagcagtttc ggggagatgg ggttcttggg aaatgagccc tccacccatg ggatctgatg 57240ctatttccac gtagataatg tcagagtcgt tcaaaccaga gtgactccat cctgaatagg 57300ggctgggtaa aataaggctg agacctactg ggctgcaaca tgatgagacc ctgactctat 57360tgaaacaaaa caaaacaaaa caaaacaaaa caaaacaaaa aacggccagg cgaggtggct 57420cacgcctgta ataccagcac tttgggaggc caaggcgggc ggatcacgag gtcaggagat 57480cgagaccatc ctggctaaca tggtgaaacc ccatctctac taaaaataga aaaaaaaaaa 57540aaaattagcc gggcgtggtg gcaggcgcct gtagtccaag ctacttagga ggctgaggca 57600ggaaaatgac gtgaacccag gaggcggagt ttgcagtgag ccgagatcac gccgctgcac 57660tccacactgg gtgacagagc aagactccat ctcaaaaaaa aaaaacaaaa acctctttgg 57720ccatctattt agatgagttg gaatgctact ttgattggtt ttgccaattt agatttttgt 57780aattagggta gtttaaaaaa actctcaaat tactgttatc ctttgttaaa aaccaaaatc 57840ttttattatt agtcttctgc ttacaatata agtaaaataa atgttttgta ttaataactg 57900gattgtatat tgcatggtta ccactatgta acaaaattaa tagcttaaaa ttacaagcgt 57960cattttaaaa ttatttttca tgtttctggg gttgactagg atggctaagt ggtttttgct 58020tggggtccgt cacacggttg ctgtcagtgg ctggggttag agtcagctca caggcttcct 58080aactcatatg gtgctggagg gagtgtctct tagcatgcta atgcttcata atttgtgtat 58140aatgaacagt gaggatgacc agaggtcact ttcattgcca tctgggctgc aaaactcaag 58200gagttgaagg ctcttccggc attacttgtt ctccatgtgg tctcctcagg atggcagtca 58260cagagtaggc agccttctta tgtgctgacc tagggcccaa aatctgtatg tgtcagttga 58320ctgagcccag atggaagctc tattgctgtt tacgccctag cctcaaaact actctttcaa 58380gaaaaattct ccaaccgagt ttttcctcta ctctcacacc accacaacaa tagtcaacat 58440aggagacttc tatgatcaaa ggtgtaggga tttctcccca ccaccaagca gtgaacccca 58500gctgggtgtc ctccaattca attctcacac tgttattacg ggaaaggtgt cccaatccag 58560tccccaagag gttcttggat gttgcacaag aaagaatttg gggagagtcc acaaagtaaa 58620ataaaattta ttaagaaagt aaaggaaaaa aagaatggct actccgtaga cagaggagct 58680ccgagggctg ctggttggct attttaatgg ttatttcttg atcatttgct aaagaagggg 58740tagattattc ataaattttc cagaaaaggg atgggcaatt cctggaactg agggttcctc 58800ccctttttag accttgtagg ttaacttccc accattgcca tggcctctgt aaattgtcgt 58860gacactggta ggagtgtctg ttagcatgct aatgcattat aattagctta taatgagcag 58920cgaggacggc cagacatccc tttcattgcc atatgggatt tggcaggttt tggctggctt 58980ctttaccaca tcttgtttta tcagtggggt ctttgtaacc tgtatgttgt gccgacctcc 59040tatctcatcc tgtgacctag aatactaacc tcctgagaat gcagcccagt aggtttcagc 59100cttattttac ccagccccta atcaggatgg agtcgctctg gtccaaacac ctctgacatt 59160atccacctgg aaatagtgtc agatcccatg ggttaagggc tcattcccca agaccctaac 59220caccctcacc tggcccagac acaagtcaca agtcctgtcc tctggaatgt ctgactgaga 59280ggcatcaagt tggagttccc atgaccccct cttctggttt gattaattta ctggagcagc 59340tcacaaaact cagggaaaca cttaggttta gtggtttatt ataaaggata ctgcaaagtg 59400tatagatgaa gcgatgtgta gggtgaggta tcgggggata gagtgcaggg cttccatgcc 59460ctcccggggt gtgccaccct ttaggaacct tcatgtgttc tgctatccgg aagctcactg 59520aactcattct tttgggtttt tatggaagct tcacgtcaat attccttccc ctggggtatg 59580aggcaggacc ttcaccggag agggtctttt attttatttc attattttta aaatataaga 59640tggggtcttg ctatgtagcc tagggtggta ttgaattcct gggcccaagt aagcctcccg 59700cctctgcctc cgaaagtgct gggactacag gcatgagcca cccagcccct ttggagagga 59760tcttaagact cacagttaga aaggagggca ggagaaggtc agagagattc tgcttcctgc 59820ccctgaggcc taacacaccc agcattataa caaaagactg taacaagggc tatgggagtt 59880accagccagg aactgtaaat cacacagtat tatttctgcc ttactcttat cagtcatgat 59940ggttacaaag gcctgtccaa gttcaaaagg aggaaaaaag cactccactt cttgatgagg 60000aaggtcaggg ttctggaaga gcatggggga ctggaaatat tgttcggcca tttcatggaa 60060aatacagtct gtaatagaca tcagtgataa atggggagat atggtggatg tattgttttc 60120ctctgagtgc caaattgggt tctaagattt cacaggccag atattattga agtggctacg 60180ttgtctgggg tatatacctt ggggttcgtc attttgtgcc aggaaaattt aggacaagga 60240ctcacacgag gagtttagga gtggaggttt aataggcaga agagaaacag aaacagttct 60300ttctgtaggg agagagggat cttcgaggga aaagaccatc cagcagcaga tgagctggat 60360tttatagtca ggtttgagga ggaagtgtct gatttactta gggctaacag gttggtttga 60420tcaggtatga cgtttacata gcacaccggg aagtctggtt gccccaccct aatcctttta 60480tgcaaatgga ctttcctagt tgattggagc tatcttgtct gctccttact gtacaggtgg 60540ctgacaaaga gaagggaaga tggagccgcc atcttgaaca tgattgacgc agctgtggat 60600atctatgtct gcagcttgat tttacaggct gctcttcttt agaaaggggc tgcttttcat 60660taaaacaaaa accttactga ggactcttgt accctcacta tctgcaggtg atttcttaac 60720tcctgtatca ttattatagt gtcataggaa tctaggaagt gtgattgcct tctggagaga 60780acttcagggt ccctggattt tctcactaat catattcatt tcattccctg tttacctgtt 60840taataaatgt tgagtggcta ctatgtgccc agggctgtgc aaggtgcctg gaataggatg 60900gcaagcaaac caaccatgac cttgctctca aagaattgtt ttctttcttt cttttttttc 60960tgagacaagg tcttgctctg tcgcccaggc tggagtgcag tggcctgatc tcagctcact 61020gcaacttcca cctcctggct tcaacagatt ctcctccctc agcctcccag gtagctggga 61080ttataggtgc ccaccaccat gcccggctaa tttttgtatt tttagtagag acagggtttc 61140atcatgttgg ccaggctagt ctcaaactcc tgacctcaag tgatccgcct gcctcagtgc 61200cgagattaca ggcatgagcc actgcacctg gcctgttttc tgtctttttt ttttaacccc 61260cacatggaaa gttaggcagg gatttaattt caaagagttt cttcccaaat attgtggtga 61320aacatctagt ccatttatgt ttcaggcttt ttcatagata ttactgtttc tcttagactg 61380acagacttag gacatcacat gattgaatgt caacctgact tttaagttca ataatagttt 61440cattttttaa atgcaaaatt aaataggagt aatatccttg aacatgtttc tccttcactc 61500atcggaccta ttgagtctag aatccatttt attttgagag ctccaactac atgtggtttc 61560tgttaatatc tgaaagtaat ttttaatatc tgaaagtttc aaatagtgat aatatttgaa 61620ggtttcaaat agtggaggag agacgcaaac tgcgagtagg gaacgcggat tgaaggaaat 61680gaaaagttga taataggcac ttcattttca gattataaca aatatttagt gaaataaagc 61740ataattttaa aaaatggata agacatgtat gtactattta atgtgtacta ataaatgaat 61800gctcatattt gccatccaga taaagaaata gaacagttga acatcacaga agccctcgcg 61860tgtcccattc agatcacaaa ctctatcttt ctactggtaa ccattattct tacttttgtg 61920ataacctttc tttgctttcc tttatggagt gtgtagattc ttaacactat agttttgcct 61980ctttttgaac ttcatgtaaa tgaaaaaatg tatatatttt gtgtttgtgt gcatgtgtgt 62040gtgtgtgctt gcacacgtgt gaatacccct tattgtttga gcttagtatt atgtaagatc 62100taaccaggaa ggaccaacct aacatttgtg gggcctggga cctaagtata gacagagatg 62160acatggtcca ctccatatct gttcccatcc cagttctgcc ctgtgctaca aggggtcttc 62220cagacactgc ataggtaccc ataccacctg caggcagatg acctttgcct gtcctttgga 62280gttaggcctg ggtaccctac tagtggtgtc tgctcttggg atgataaacc cgaggggctt 62340atcagcttta tatatatata tatatatata tatatatatt tttttttttt ttttttttag 62400ctagcatctc tctcgttctt ccaggctgga gagcagtggt gtgatcttgg ctcactgtaa 62460tctccacctc ctgggttcaa gcgattctcc tgcctcagcc tcccaagtag ctgagattac 62520aggcacgtgc cactatgcct ggctaatttt tgtattttta gtagagactg ggtttcacca 62580tgttggcatg tgagccacta tgcccggcct cttttttttt tttttttaag agacagggtc 62640ttactatgtt gcccaggctg gtgttgaact cctggcctca atagatcctc tgtccttggt 62700ctcccaaagt gctggctcag tcattatgtt ctttactgcc atccattgca gtataaaaag 62760aataacagtt ttccctcaga atattcttgg tgaaacagta acaattatta attttattaa 62820atcttggctc ttgagcaaat gtcattttaa tattctgtgt gataaaatag caatgtcaca 62880taaagtgctt ttacatactt aagtactatg gttgtctgaa gaaaaaggag ttgtgtgatt 62940gtcttgagtt tgtaagtgga actacttttt tcatcgagca ccgtttttac ttgaaataac 63000aaagtatgaa tatgaatgca gatttggcca tttggcagat ttttatttat ttatttgaga 63060caaggtcttg ctgtgtcacc cagactgggg tgcagctcac tgcagccttt acctcctggg 63120ctcaagtgat cctcctgcct cagcctcctt agttgctggg accacaggtg tgcagcacca 63180tgctcagcta atttttaaat tttttgtgga gacaaggtct gaccatgttg cccaggctgg 63240tctcgaactc ctgggctcca gcaatcctct cgcttcagct tctcaaagtg ctggaattac 63300aggcgtgagc cacggttccc agctcgcctt ttcatatgtt tattgggttg ctaaatatgt 63360tcttatttga agtgcccact tgttcaagtt ttttgttcac ttttttattg ctgtctttat 63420aattttttga tgacaagaaa tatgtttaaa ttaaaggcag ttttgtcaat ctgccttatg 63480tttggaattt gttgtgtctt taaagactct tttcctgccc ttatattata aagatatctt 63540atagtattga tattgtcatt cacagttagg tctttaatcc tagaagttga tttttgtatg 63600aagtaagggc ccaatttatt tttttccacc tatgtatacc cagttttccc agcaccattt 63660aaacgggcgg tactttcccc tctgatatgt catgatgaca cctttgtcat gtacacatga 63720gtttgcttct ggatctctat ttgtgttcag ttgttttact tgtctgcata aatgccacag 63780tcttggtttc tcagtcatta taatgagcct tgcctgctag gaagggtcct tctactttgt 63840tctccaagag tgccttggat attcttggtc attttctttc catataattt ttagatttgg 63900tttatcaagt cgataaactt ttgtcatgca gttttttaaa agaaaataaa gtgccctaat 63960gtgatttttt ttaatttgga ttacattgaa tacataaatc agtttgggga aaatcaacat 64020ctttataata ttgaggcttt ttatccatga gcatgaaatt gctttctaca ttaataactt 64080ggtaaagttt tatattttcc ttatggatct ttcacttctt ttgttagatt tttctccacc 64140taagtactgt atcttttaat tctactgtaa atagtgtttt tattttttaa ctgctgctat 64200tacataggaa tataattttg catctggcca gcttgcctaa acagatgatt tcaaaatatt 64260atctgtcaga ttttctgtgt tctctatctc tgtaatcata tcatctatgt tttatgatct 64320atgacagtta tattttttca tctccaagct gatattttaa atttcattat tcttgcttta 64380tactggttgt acatattcag ttagagtgat tgcagtaggc aatttgcgat gttcccaatt 64440tgataaggaa agcttttaca ttttaccatt aagtataacg tttgcgagct tattatagct 64500atcctttgtc acttagggaa gttatctttg ttttttagtt atctaggaaa ctaaaaaatc 64560agaaaagtta gtttgatttt atcagataca tctgctacat ctaatgagat gatcatatag 64620tttttttcct cccataaact gtgaatataa tgaatcacat taattgattt ttttaaatgt 64680taaaccaatc tccatttctg ggataaattc aacttagtca tgttgtatta gccttttgta 64740tatcttatat ctataatact gaatgagatt atcatactct ttacatgtat ttgaagccat 64800gtcattaagt gcatacaatt tttattaaat ttttaattga caaataattg tatttattta 64860tggggtacga tgtagtgttt tgatatatgt ttacattgta gagtgactaa atcaagctaa 64920ttagcatact catcactgaa catatttatc atttcttgtg gtgagaacat ttgaaattta 64980atctcttagc aattttgaaa tatatgatac attattatta actacagtca ccatgctgtg 65040cgataggtct caaaaactta ttcctcctaa ttgaaatttt gttccctttg accaacatct 65100tccaattccc caacccctag cctcctctgg taaccaccat tctactctct acttccatta 65160gtttgacttt ttcagtccac atatgagtga aatcgtgcag tatttgtctt tctgtacttg 65220tcttgtttca cttagcataa tgtccaacgg gttccccatg tcattgtaaa tgatggaatt 65280ttctttttta tagctaaata acattccatc atgtatacat accacatttt ctttatcgat 65340tcatctgttg atggacagtt aggttgcttc tgtatcctgg ctattgtgaa taatgctaca 65400ataaacatga gagcacagat acctcatgct gatttcaatt cctttggata agggtcccca 65460aaccccaggc tatggaacag cagtggtatg tgtggcctgt taggtactgg atcgcactgt 65520aggaggtgag cagctgcgag tgagcattac cacctgagct ccatctcatc tcagatcagt 65580ggcagcatta ggttctcata ggagtgtgaa ccctattgtg aactgtgcat tgcaggaatc 65640taggtggtgc actttttatg agaatctaat gcttgatgat ctgaggtaga atgattgcac 65700tctgcaagac tccccacgct catccctgtg gaaaaattat cttccacaaa actggtccct 65760ggtgccaaaa aggttgggga ctgctgcttt tggatatata cccagaagtg ggattgctga 65820agcatatggt agtttaattt taattttaat ttaatttagt ttaattaatt tatttttagc 65880acctaggctg gaatgcagca gtgcaatcat agctcactgc agcttccaat tcctgacctc 65940aagccatcct cccaactcag cctcccaaat ttctggaact acaggaatga gccatctcac 66000tcagccctat ttttagtgtt gggaagaatc tcaaaaagta atgactgtac taatttacac 66060cgctaccctc agtatacaag ggttccatat cctcactaat acttatcttt tatctttttg 66120atagtagcca ttctaagtat gtatagtttt aaaattatga agtttaaatt gaaccttagg 66180aagttgctac tctgtcacca ggctggagtg cagcagcgtg atcttggttc accacaatct 66240ccgcctcctg ggtttaagca attctcctgg ctcagcctcc caagtagctg ggactacagg 66300cacatgctac catgcctggc tcatttttat atttttggta gagatgggtt tcaccatgtt 66360gtccaggctg gtctcgaact cctgacctca agtgatccaa cagccttggc ctcccaacgt 66420gttgggatta cagacgtgag ccatcacacc cagccttgaa gttgcctttt ttatcttcag 66480tagtgcttct tggcttaaat tcttttgttt tataaatagt aatggaagct tgccagtttt 66540attttagaaa gtatttgcag gccaggtgca gtggctcatg cctgtaatcc cagcactttg 66600ggaggccgag gcaggcacat cacttgagcc caggagttcg agaccagcct aggcaacatg 66660gcaaaacctc gtctctacaa aaaatacaaa aaattaactt gggcgtggtg gtgcgcgcct 66720gtagtcccag ctactctgga ggctgaggtg ggaggattgc ttgaacccag ggggtagagg 66780ttgcagtgag ccaagatctt gccactgaac ttcattcagc ctgggtgaca gagaaaaaca 66840actctgtctc aaaaaaaaaa aataaataat aaaaaataaa gtatttgcat gatatatctt 66900tttctgtctt tttgattcag atattgtcag ctgagtccaa tctaacaaac ttatatttta 66960accgaagctt tagtactgtt atatttaata aactaataat atatttgcac ttaaatacaa 67020catctaattt tatgcttttt aattatacat gatttgtatt tctttttttc ccatgtaagt 67080ttttagggta tacatcttta aaggccttac ttttcattat cgttcagttt aacttatttt 67140ctaatttcca tttttcttct gtgacctatg gtttagttag tggtggattt attttccaaa 67200atatggatgg tgtccagtca aacttttggt attgatttct ggcttatctt gtgtttggaa 67260aatatgtgaa ttctacagct ggtctgtgta agagttctct gtatcagtta gggaagtttg 67320ttcttcctgt tgttcatatc ttgcatatct ttactaaggt ttagcctgtt tgttctataa 67380attacttaga gaagctgtgt taaattttcc cactaaaatt attgattttt gtctttctct 67440gtatttatca gtatgtatct actgaagtct tttcaaatcc ctgatcagtg gtttgttcag 67500gacagcactt tgattgaggg aggtgacgtg gcttaacata gtatggtctt gagctgcctg 67560gtttctgtga tttagggact gaaccagctc tggtcacatc tggattatct actatccagc 67620attcaaatga accagattac atgaaaggat atgggggtac tctttggggg ccacggtgcc 67680acaaggcctt tggtttcgat ctccattgcc tagggaatta acctgtgctg tgtgattcta 67740gatgttttct tcctgctccc ttaaataaca cctaaatgtg ttattcagca gtgtggctcc 67800tgctaagcag aggagaactc ggaattccta ccaaattctg ataataaaat aactttcctc 67860cacctcaacc attgttttta ccagtcctgt caactgttag ctttcctgga tttaatgatc 67920tcaagttgag gtcaatgtca acagctttat gggatgaata agatgaacgc ccataggaaa 67980gtcagtctct tgaacacggg ttgttttctt ttggttaccc tctaagattt tttctctttg 68040atctccagtt atttgaagga ttgaaggcat ttcgaggagt agataataaa attcgactgt 68100ttcagccaaa cctcaacatg gatagaatgt atcgctctgc tgtgagggca actctgccgg 68160tatgtaagtg taggagtttc ttttgtgttt cttttaatgt aacgggtcac ggtgttgacc 68220accaaataaa taatttctga atagttagat aaatattcag tacaaaccat atgaacatta 68280acattatttc tgatctactt tagttaggta aaaatacaag aaaatggccg ggcacggtgg 68340ttcactccta taatcccagc actctgggag actgaggtgg gtggatcact tgaaaccagg 68400aattggagac aagcctggcc aacatggtga aacaccatct ctgcaaaaaa tacaaaaatt 68460agccgggttt ggtggcacat gcctgtggtc ccatcggtgt ggctgaggca tgagaattgc 68520ttgaacctgg caggtggagg ctgcagtgag ccaagataat cacatcactg ccctccagcc 68580taagccgcaa agtgagactc tgtaaaaaaa aaaaacaaaa aacaaaaaac ccaagaaaat 68640aatatcattt ggcaattcca caatttttta aaatcagtgt ctgtggggga ttcatatgca 68700agtgagagat gaaagagtaa ggaagaaaaa tgtatctcaa cctaaaataa tatttgaaga 68760ccacatgaaa ttaatattga aaatggaaaa tatggtgtgc agcacaggta ttttgcggat 68820attttgccta attgctttag atgctagcaa gatatagtaa cttaattatt ttgatatttt 68880atcttaagta atgttttgag ataaaaagat atcaaaatgg tttctcatgg ccattgaatc 68940gtggctgtca caatgtttct tatggagcag aaatcattgt aagatgggtt agattttttt 69000tttgagagag agtctcactc tgtcacccaa gctatagtgc agtggcacaa tcttggctca 69060ctacaacctc cacctccggg gttcaagtga ttcttgtgcc tcagcctcct tagtatctgg 69120gattacaagt gcacgcagcc atgcccagct taattttttt aaaaattatt tttagtggag 69180acatgatttc accatgttag ccaggctgga cttgaacttc tggcctcaag tgatctgcct 69240gcctcagcct cccaaagttc tgggattaca ggcatgagcc accgtgccca gcttcaggga 69300tttagcccaa cctatgcatt caggaagcct gaggacggct aaatccaagt gttcttcatt 69360cctctgccta tttttgtaac ccgcatttca cccatctcct ttggaggcca taatatagta 69420gcagagggga aattaaggta aattctttgg actagggcat agtttcgctc ttcttctcat 69480tacagctaga tcactgggga aaagtcttta aaatggggct ggaaggaaag ggaagtaata 69540tttgttagac atcaattttg ctaccaaact gtgttatgta gtttcacatt ccttatctgt 69600gtaatcacag cagtaaggcg ttgctaagaa gattatttgt tgtacagttt attagtgcct 69660ttgtacagag aagaaaactt gagtccagag agattaaatg acttgtctga agtcacaaag 69720agcaaaagga cagggcaaga aattagatcc aggtgttttt attcctggtc aagttctctt 69780ctcactgaat tctgtctcta gacagcaata ccaggggctg aggcaggtgc tacagggttc 69840acctatatga

ttggcagtcc caatttctat aacattacta cattattatt gctgttacag 69900gtcaatattt aaatagacaa attctgactt catgagcttt actcagatgc ttatgactga 69960ctcatttcta ccttaggtga cccatcacat ctctgaaagt atgtttctct actttgcaag 70020tgagcagaga ctaaattatt ttatgaagta tcacccatct agtagatgta attttttttt 70080ctttagaaat aaagtgctct ttgcttttgc ccattttcct attgggttat ctatctcttc 70140attgactttg gggatatcca aatatatata ccagttaaaa ttctttgttg atcatgctac 70200caataacttc acccagtttg ttgctttaca tcttttgaag aacggaagtc tttaagtttc 70260aaatagtcac attttatcca tttttttcct tcatgatttg tgttttacat ctcctactta 70320agaatccttt cctaccttaa ggtcacagag atattttgta ctttttaaat aaagtcttag 70380tattttgtca catttaagta tatcatctaa ttagaattga ttggggggta tggtaagatg 70440tagggatcta atcttatctt tcacatgtgg atagctcgtc atcccatcac aatttttggg 70500gggaaaatca gaaaaaattg tttggtttta ttattacttt aaaatttttt ttattggtac 70560cataaattat acatatttat gaggtacact gatgttttca tgcatgcata taatgtgtaa 70620tgattaggac aaataagaaa gaaataaata aaaattagga taattaggat atccatcacc 70680tcaaacattt cttatttttt tgtgttggga ttattaattt tttaacagtt taaatgcttc 70740agtgaggatc atttattatt gccacattgt gagaaaattc tgtcatttat tatgtttttc 70800attctttcag gtatttgaca aagaagagct cttagagtgt attcaacagc ttgtgaaatt 70860ggatcaagaa tgggtcccat attcaacatc tgctagtctg tatattcgtc ctacattcat 70920tggaactgag gtgcaaactg actctttatt ttggggtact ttgctgggca agttattatt 70980gtttattgtt gtttgaaact tctagcatat agtttgcagt agccccccag tagcatcatt 71040aatgacttct tccttctgat tgtcaagatt agaggtagca aacattttct gtgaagcgcc 71100aatcagtaaa tattttttgg ctttgtggcc atatagtttc taataagaaa ttagatccct 71160acctcttacc ataccccaaa atcaattata attcgattat atacttaaat gtgacaaaat 71220actaagacgt ttattaagaa atacaaaata tctctgtgac cttaggtagg aaatgatttt 71280ttttttttga ggtctctctc tggttttttt tttttgccca cgttgtcgct taggctgggg 71340tgcagtgatg caatcacggc tgactgcagc tttgacctcc tgggctcaag tgatcctcct 71400gcctcagctt cccaagtagc tagtactaca ggcatgtgct accatgccta gctaattttt 71460aaattttttg tagagatgat gtctcactct gttgtcctgg ctggtctcaa actcctggcc 71520tctagcaatc ctcccacctt ggcctcccaa agtcctggga ttacaggcat gagccacttc 71580acctgaccgg agaggattct taaactctgc cattttagta ctaaagcagc catagacagc 71640acataaatga gtaaatgcag tgctgtttgc cttgcccaat taagactagt cattattttc 71700taagtttaca agtgcagtgc ctcccattgt ggcagtactt ctctgaggta gaaatggttt 71760taaaatttag gggagggaga gctgctaatt ttcattttca tgaggtcttg ggattacttg 71820gcatggagtg agaatggagg ttccccttcc cacatagaaa aatggtgaaa ataaagttca 71880cagtgggagt taaggaagga aattgaagag ctgggatggt aggtttaaat aacatgacct 71940tatgatttcc tggtgggtca cagtctcttg gttgggtgcc cttgtgaata aaggcatgga 72000ttgggcatgc ctggaggggc caaggccttt tgagcggacg agtatgttta tatgaagacc 72060ctgtcacctg tctctggtat ctgctaggca gctgtggctt gagagtgtga tattgaggga 72120taattgatgg aaggagattg aatgtggctg gcaggtaaag agatagggaa catatggaga 72180tatttagaat aagagagtgt gagatagagc gcttttgcta tagcctagcc attctgttct 72240ctactaagtg ttgcggggtt accaggtttt ctactaggct gtatgaatgc aaaaggtaga 72300gagatatata gggccatgga ataaataccg aagtgttttc tttggtatcc ttgatacctt 72360tcgaaagccg tgtaaggatc tagataatga atttcgtgaa ttgcagtctc tctgacaagt 72420tttaaagaat aggaacaatt ttaaaaagtc atctacttcc ataagttttt tgacatttta 72480agataattga attttttttt ttcagctttt aagttccagg gtacatgtgc aggtaggtgt 72540gttatatagg taaatgtaag ccatggtggt ttgctgtaca aatcaaccca tcacctaggt 72600attaagccca gcatccatta gctattcttc ctgatgctct tcctcctccc gccccttccg 72660acagacccta gtatgtgctg ctccctgcat gtgcccatgt gttctcattg ttcagctccc 72720acttataaga gaacatgcag tgtttggttt tcttttaata ttatttttaa ctttatgata 72780ggaaggagta ctttttaaag ttggttgaaa cattgttact gatctcaaag cactaccttc 72840cagttattct gagatacttt ttcagtctaa gatctgatac tcctattcct ggtttgttga 72900gagtttttgt catgaatgga tgttggattt tgtcaattgc tttttttgaa tctcttgaca 72960tgattatgtg gttttgtact ttattacatt attaatgaat gaattatatc aatttatttt 73020tggatgttaa atcaacctta ttttcctaag ctaaatccta cttggtcatt gtgaataatc 73080cattttttta tcttgctata ttcagtttgc taatatttta agaatttttg tttcactgtt 73140catgaaatat attgatctag ttttcatttt tcttttcttt cttttttttt ttttttttta 73200catctccctc ctcttcctct tgatctagtt ttctaataca gctgcactcc aacttacgat 73260ggtcctactt aggagttttt gactgtatga tgtttgaaaa caatatgagt ttagtagaaa 73320cttactttga gtacacatac cattctgttt ttttgctttt agtacagtat tcaataaatt 73380atgtgagata accaatactt tattataaaa taatacactt ttagatgatt ctgccctacc 73440ataggctaat gtaattgttc tgagcacatt taagatagga taagctaaga tacgatggat 73500gtttggtagg ttaggtatat taaatgcatt ttcaccttaa ggatattttc aacttaggat 73560gagtttattg agttgtaacc ccatcacaag ttgaggaaca tctatgtatc taattccatg 73620attcagtaaa ttctttagac tgccaaaatc ctgtaatcta gagttagaca agatcttaaa 73680tcaggttttg tggtccatct tgtagtcatg atcattctca ctattaggga attcttaact 73740ttttgcattt gaatcaccga ggtgttattt aaaatacaca tatggaatcc aagctccaga 73800gactctgagt agatctggtg agtgattgtg atgcctgccc acattcaaga accttagtac 73860aaaagccctg ctgaatggtt ctctttcact atacactcta tcaacttatg tacttgatca 73920cactttggac ctcaaaatca ataattttta aaaatctact tcctaagttg tgaggtacga 73980attgaaggaa ataatgaata ctatttgggg agtcaacatt atttattaac gaataccatt 74040tggggagccg acattattta tatttggttg gtatatttgt atcaactatc attttctaat 74100taatggtata ggcagaataa accatcactt gtgattcaga aaggaacatg atacaaataa 74160catccaataa tgtatatgga tttaaataga tctgccccct acagatgtta cgcaattcat 74220gttggtaatg atcattcatt aggttttcgt ggtggctaca tttgatatgt gaagtactgg 74280ctggaagact ggtgccagta gcttcaggtt tgctgggatt ctttcatcag agatgactag 74340ctttacttat ctttttatgt tgcatgtttc tatgatgggc ctatcctgtc attgtcttca 74400tagtataatt gcaagctcaa ctctgtcagt tatgtgattt tttttttttt tttggtcctg 74460tcttgctttt ggctgacttc tatatgtttt tatttcatgt ccttttcata gttagattaa 74520ctgggtctta tgtccaagag atattttgat ttctttgaat gaataaatct atgttaggct 74580actgtattag gttttataga cacctagttg atcacttgtg tccagtctct attccctggt 74640atggtagttg ctgtgtttat agaacattga ggattctaca atggacacat tggtgttggg 74700ccccagccca gacccaaatc gaaatttcta gagccaggat cagagactct gcattcaaca 74760aactctccag agatttcata accactttta aaggactcac catcccaaac cttgttaagg 74820aatgaaatat atgtctgcca gtaatttcag tgctttaagt cattgaaagc tgaactttta 74880atggcaccaa agtggaaata tttatataat tgaaagctaa acttcatcct aatggcagtg 74940ttgagttcac ttccataggc cctgatataa cagtctaata ttattgtttt tcacataaaa 75000taagattcag tcactgccat ataattaggg agtggctctg ctattggatg gacttaaaat 75060atttcattat gtttgccaag ctctgtctct ttacatgttt tataattaac tgatccttca 75120tttttatttt gttttatttt atttttgaga tagagtctcg cttggttgcc caggctggag 75180tgcaatggtg caatcttggc tcattgcaac ctctgcttcc caggttcaag tgattctcct 75240gcctcagcct cctgattagc ggggactaca ggtgcgtgcc accatgccca gctaattttt 75300gtacttttag tagagacggg gtttcaccat gttggccagg ctggtcccaa actcctgacc 75360tcaggtgttc tgcccacctc ggcctcccaa agtgctggat tacaggcatg agccaccatg 75420cccggcctcc ttcattttta ataatcttca tagatacata cttgttgtac taatgttttt 75480gtgcagttcc tcatgataaa taattaaatc aattactaaa atccttatag atttatgatg 75540ataataaatg gaagtgtgta ttattgaaac atgtttaatt aactgttcat atataaccag 75600tgagtaggga ttggcaatta aaaataccag gctaccagtg catggaaatt tgaagaaaac 75660aacaacctga aattcagaat actccaaaat ctgaaacttt ttgagcactg acatgactaa 75720aaatgctcat tggagcattt cagatttcat tttttcagat tagggatgct gaattggtaa 75780gcataatgca gattaatcca aaatctgaaa aaaatcctaa atcaaaaaca gttttggtca 75840gaagctttgt ggataaggga tagtccaagc tttttggact gaagcttttt ggataaggta 75900tagcctataa tacataaata cataatacag gataatcact gacctgaatg tatagcatca 75960gtatggtaca caaatattta aatccatgta ctttgttgga tattatgtta tataaacttc 76020ttgtaaaaag tttagagagt aaaatcattc acattaccaa aagatttctc atatttataa 76080aaaggattat agcagcattt taatcagtat ctcctaaagt atttatttat gggttgttaa 76140atctaaaaga gaaactacag tctggagggc tctaaactac tgctgattac atatcagttg 76200ggaattaaga gaaaatctca gatcataata tttaaataaa aacatttaca tgaatgattt 76260ctaagttttc actttactag acaagaaact aaaattatat gactgtcatg ttcaatattg 76320gatacttaac aacactacat ccaaggaagc caggttttgc tgattttaac ctcgtcctgt 76380tgagtaactc catgcaggta cagtggtaca aacacatgtg gacacacaga cccagacctt 76440tatttcctcg gggattctgg taagtgtaga ggtgtcttga ccatagtcaa tagcagaaat 76500atgcacaacc acaagctctg aaattccatt tgattgttgc tcttagcctt ccacttttta 76560ggcatatgtc agtcccattt catcccaccc actctctcca tttgggaggt ggtagagtga 76620gacaatactg aactatacca gggctgagaa taagtgtctt tgaaaagggt cgaatctgtg 76680atgctagaga cagccctgga aactgtcagg agttagccca accaggactg tgaccagatc 76740ccaggctgtc caccacagat ttgcaggcta cctgcagatg tgactttttc aaatgtactc 76800aaagacaagc tgactttggc taatgcagaa attaattaat tcctcttttt cagtaaactt 76860tatcctccta cacttagatt gtctgtaagt acatctctgg agttgagctc aactagaaag 76920aagctgtctg catttagtta ataccagcat tggatgcaca caatataatt tgaataatgt 76980agagcaacat tttaatcatc tctcataagc agtttcccca tttgcaactt cctgggaaat 77040cttacattat gaaatgttca ttagaactcc cattttaaaa ccctgctgcc attttgtgag 77100tgggcagaag aaaggctgga gatgagattt gtctgtctca aatgattcac tccttcattt 77160ctggttcact ccacagggag cttaaggaca tgtgcgtttc atagacatgc ctttcttttc 77220cttttatcac cttgttaaat cttaagattg aacatacaat tcagcctgta atcatatcaa 77280ttcccatgaa aaatattttc cttattcact gcctctattt gtgcttatac atctgatcat 77340ctttttcctt tactttacaa ttagtttcta tgaacagaag aatctgaaag atttaaagac 77400tagttagcac agcagcaatt tataaatcat taatttgggt actgtctata catttaatgt 77460gttctttttc atagtcctat gtgaaataca tatacatata tatatattcc actgtttata 77520aacaatattc agttttattt gcataactca atatatttta tattaacagc tccgttttta 77580gtgtcttaag acatcgagtc tgtttttaga gatacagtct atttgccttg attttagcct 77640gttataatca gcttattatt atctggccac tcttaccagt gagtatcatc ttgaggctgt 77700tcttgctcat ttcaacttgt cacaggggat gttttttact ctttggagtt taggtacacc 77760aggttattaa ttatgctcct gattcatggt acttccatca tggggcatat aaggtccctg 77820tctttgtttt attcccttct atcttcattc accactctca tttcctctct ctccactaga 77880aataattctc aggaatcaaa ttaatattat tctggcttat atgtgttttt aaaaatctca 77940tcgcttttta tacatgtaat tttaatttat gtaagagact ttgtcctaca gatttcattg 78000tgtttcttct ctttttcgcc cagcactgtg tgttccattt ctatccagtc tactatgtgt 78060acatcaagtc catcatttct aactgttgca tagttcatga tgcgaggcat cttccacatt 78120gtatcccaat tccctaactg gaatcccagt tccctgctac ctcacacaat gctccagtga 78180acagctggaa aatcatacaa cccaaggaat tattgaaagt gattatatcc cagcaaaagg 78240cccaggccca tcttacactt ccaccccaag aaggtactgc tacttttcgg gaatggcctg 78300gtctccttgg cgaaattggc atttgatctg ttctcatcac tgtcgtctgg catcagaagt 78360gaccccactt gtcaggcact gtactcagtg ctttccatgc actaactctg ataacaatct 78420tttttttttc tttttttgag acagagtctt gctctgttgc ccaggctgga gtgcagttgt 78480gtgatctcag ctcactgcaa cctccacctc ccaaattcaa gcgattctcc tgcctcagcc 78540tccccagtag ctgggactac aggcgtgcac cactacacct ggctaatttt tgtattttta 78600gtagagatgg ggtttcacca tgttggccag gctggtcttg aaatcctgac ctcaggtgat 78660ccacttgacc tcccaaagtg ctggaattgc aggcaagagc cactgagctt ggcctgataa 78720caatcttgtg agcaggtgct tatgcagtat tttagggatg tgaaagtaag gtccaaagcg 78780gtgaaataag agcctgtatt ctcttaacct ccatcccgca acatctttta tgtgtcagtc 78840cctgcactaa gtctagggat actgtgctga gcaaaaacta tcttcttgct ttcacagagc 78900tcagtgtctg gcagggggtc agactttcat aatataaacc cactaaatga gtgcatattg 78960atggcggtca ctgctgtgaa gaagtgggaa tggttagcat ggaaacatag ccccaatggg 79020ggcgactaag ttctttccca tctcattcta ctatgtctac tttcatctct acttttttct 79080tttctgagct atcagctttc ttgctctcaa ctatatttga tgtatttaac cagattttat 79140atattgtatt atgtatttta taacatgtat atatatcata taacatacac atatacatac 79200atacacacag ccaattaagt ctcaagttca attacaatgc ttctaagttt aggactattc 79260attttcattt tggcagagaa attatctggt aaaaaattca agtagaacca aaggtataca 79320atagatggga agtttccttt tcactctcac actctcattt ccatccaggg ttctacaatt 79380catctccttc caagcaattc ctattgccag cttttcttat accctttcag aaatacacac 79440acacacacac acacatatat acacacacac acacacaccc ttacatgtgt ttgtacatta 79500tctctctttt tacaaaattg gcagtgattc tttgtcctgt ttctgccact actcaaaaat 79560tttaaaacaa attacacacc tataaacata caatttaaag aaaagagtga aagtgaaaat 79620ctaaggaccc agcacatggt taagatgaga gcatgatggg ttcaatggaa agcctttgtg 79680tacctttctc ctttgcctcc gttccctctc caatagagtc aaccacgttg gaggttatag 79740cacttccttc tttatgtccc cccatctccc atctggtatg gtattctctt ttactgcaga 79800tggacatttt ggcagacata tgtagttgct tctctttggt atttacctag gagttgaagt 79860gctgggtcac agggtgtatg tatatttcac tttagtagat actgctgttg taggactttc 79920tccttagttt agctaaagat ggggtccttg tcccaaggcc atgaaaaatt aggctcgcag 79980acaatttgaa aggtgagaat aatggaactt attgggaaaa aagggaaaca gggactcccc 80040acaaagccag ggtcctgcta gcatgcttcc tgccttgcag attgaatccc aggtaccacc 80100caggaagagg aggggccagg ctcctcccca ctgtgaatgg tgtgaccgtc tgtggctccc 80160cagtgtgcac tcctcccagt gtgcaggccg gttggagttt ctctggggtc ttcttcccac 80220ttggctgtct cactgccaaa ctcccaaagt gcttatacca gtttactctc ccatcagtgg 80280tgtatgtatt tgcttcattt ctttgccaat actgatactg tcttattaac tttcctcatt 80340ctaatgtata cagtcttgtg ttatttgtgg tttaatttcc ctgagaacca attatgttga 80400gtaccttttc ataggtttac cagctacaga agtcctcttg tgaagtgcct ttgcaagtct 80460tttgtctttt taattttttg catctttgta tattctaggt ataaatcctt tgatacatat 80520atcacaaata acttcctagt ctatggcaaa tcctatgttg gataaacgta ctgcaaatag 80580tttcccagtc tgtggctagc ttctgtgtct gtgtcttgct ttgtcacttt cttactgata 80640tcttttgatg aacagaagta cttagtttta aagtagttaa agttttcttt atgttttata 80700ctttttatgc attttaaaga aattttttgt tactccaagg tcatacaggt taaataaatt 80760cttactccaa gaacattctt ttaaagtttt gctttttttc atttaaatga aatccatatg 80820aaagtgaact ttgttatcaa gtaacatata caatttcttt tatttttctg cacggagacc 80880aagttgtccc atcaccattt attgagtggt ctatcctttc ctcactgatt acagtgccag 80940ttttgatatg tcatgtttcc atagatgaag aatattttgg ggctctctat ctgtaccttc 81000ctttttaaaa aatataaata gtggtgatac tatgaacaat tttgtttgta ttattgtttt 81060ttgcacttaa aatttgtctt ggagatcttt tcattttggc acatacggat acacccctat 81120ttttttttcc attttcctag atgtggggta tccattggac atatgtaccg tactgaattt 81180aatatagaat gtcataaatt acaagatgta acattatttt atacactgag atggagaatc 81240aaactgcaac gcagtacttc cctgatcatc ctgagtgatt catgagttag ttatactagc 81300ctcttatttc tttgaggtgt acgttttctg agggaatctg ccatttctcc tgccatgagt 81360tgcattgctt ggctcgtgat aggcattttt atttttgcat gtaattttgt aacaaatgct 81420aacactgctt tatcttcttt ttgtttttgt ttattgagac ggagtcttgc tctgtttccc 81480aggctggagt gcagtggtgc aatctcggct cactgcaacc tctgtctccc aggttcaagc 81540gattctcctg cctcagcctc ctgagtagct gggattacag gcatgtgcca ccatgctcgg 81600ctactttttg tattttttgt agagatgggg tttcaccatg ttggtcaggc ttgtcttgaa 81660ctcctgacct caggtgatct gccccactca gcctcccaaa gtgctgggat tacaggtgtg 81720agccaccagc cagctttatc tttttaaagg tttcttccta ttgtgggttt cattagaggg 81780cttggttgtt gctttgcaag aaaacattga cttgcttttg tttaatagtc ttataaatat 81840ttgtttcact aacatcaaat acatgccatg ctcctgcttt tgagcttttc tgtgcagtaa 81900cttttcttct cagtgctaaa tcataagttt ttaaagacat ttaacatggc acactcaaca 81960tgtgtcacca atgcccatag ccactggaag tatcatcagt gtcaacagct atgacgtttg 82020gcaatgacag ctttgccata actgctgctt agccaataac aattgtggaa tgctgagtcc 82080agatctcaaa catgttaaag gtaaaaaaaa aaaaaaaaaa aagatatttt cgagtctgta 82140aaacatggta gcgtatccgg aattggtggg ttcttggtct cactgacttc aagaatgaag 82200ccatggaccc tcgcggtaag tgttacagtt cttaaaggtg tcgtgtctgg agtttgttcc 82260ttctgatgtt cagatgtgtt cggagtttct tccttctggt aggttcgtgg tctcgttggc 82320tcaggagtga agctgcggac ctttgcggtg agtgttgcag ctcttaaggc ggcatgtctg 82380gagttgttcg ttccttgcgg tgggttcgtg gtctcgctgg cttcaggagt gaagctgcag 82440accttcccag tgagtgttac agctcataaa ggcagtgtgg acccaaagag tgagcagcag 82500caagatttac tgcaaagagc gagagaacaa agcttccaca gtatggaagg ggaccccagc 82560aggttgccac tgctggctca ggcagcctgc ttttattctc ttatctggcc ccacccacat 82620cctgctgatt ggtccatttt acagagagct gattggtctg ttttgtcagg gtgctgattg 82680gtgcatttac aatccctgag ctagacacaa aagttctcca cctccccact ggattagcta 82740gataaagagt gttgattgat gtatttacaa accctgagct agacacagag tgctgactgg 82800tgcatttaca aaccttgagc tagatacaga gcgccgattg gtgtatttac aatctcttag 82860ccagacgtaa agattctcca agtccccact agactcagga gcccagctgg cttcacccag 82920tgtatcttgc accagggctg caggtggagc tgcctgccag tcccgcgccg tgcacccgca 82980ctcctcagcc ctcgggctgt tgatgggacc aggcactgtg gagtgggggt ggcactcgtc 83040agggagactc aggccgcaca ggatcccaca gcggtggcgg ggggcgggag gctcaggcat 83100ggcaggctgc aggtcccgag ccctgccctg cagggaggca gctaaggcct ggcgagaaat 83160ctggcccggc gagaaatcta gcgcggcgcc ggtgggccag cactgctggg ggacccggtg 83220caccctccgc agctgctggc ctgggtgcta agcccctcac tgcccggggc tggcagggcc 83280agccggtcgc tccgaatgtg gggcctgcca agcccactcc cacccggaac tccagctggc 83340ccacaagcac catgcgcagc ccgggttccc gcccatgcct ctccctccac acctccctgc 83400aaactgaggg agccagctcc ggccttggcc agcccagaga atggctccca cagtgcagcg 83460gcaggctgaa gggctcctca agcgcggtca gaatgggcgc cgaggccgag gaggcaccga 83520gagcgagtga gggctgggag ggctgccagc actgtcatct ctcagtagca taatttatat 83580aaccagtctc ttgttgatta accattatat tattgataca acaaatataa gaactgttac 83640tagtaaattg agtaaagcag gaaaattaaa tttggtctct tactgatcaa ccattattag 83700attgttgata acaacggtta taatgttgat caaccgttat attgttgata caattatatt 83760tgatgtattt aaccagattt tatatattat attctatatt ttataacatg tatatgtatc 83820atataacata cacatataca tacacacaca cagccaatat aatttcactc tcagtttctt 83880gttaatcaac tattatattg ttgatacaac aaatataaga actgttacta gtaaattgaa 83940taaagcagga aaattacatt tgggagcctt aaagatgtag gttttcttca agaaatttat 84000gttatagtta tatcccctgt tgcatgtgaa gacatacatt caaggatact tactgcagct 84060cacacaattt gctgataggt tggatgtggg tgtgagagaa gagatgctgt tttccttttg 84120ggcgatggca actggatagt aatcagttac taagatggag aagaatgaga aagaagtctt 84180tttttgtttg tttgttggag tgatatgggt agaataaaga gttaaaacag tcatgcatgt 84240aggtactata gatgtgaaag tctattattc aggggagagt ttggaattta agggatagat 84300tcttgtcttt aagcataaaa atgcctttga aggtgagaaa ctagattaca tctttaaggg 84360gagaactgta gatagagatg aaaagaaggc aaggactaac ccctggggca ggtcagcatt 84420tagaagaaag ggagtttgta aaatgctaag ctgtctgaga agtagcagcc tgcaaggtag 84480aaagaaaaac aagagaggtt tagtggactg gaaaccaagt gaacctggaa accacaagca 84540gctgtggcaa atcctgccac agtgagatga ggcctgagaa ctgagtattg gatttgtcaa 84600tgtggaaggc cttggtgatc ttgataagca tgtgttagta gggtggtggg gttgcagtgt 84660ttgggatttg agagagaatg agagaatggg tagctgtgat gctgaatatg tataaatgtc 84720aggaggaatt ctgctgcaca gtgggacaga gaatggacgc ctccctggaa tgggatagat 84780gctaaaggga gtgtgtgtct tagttgggag atattatggc atatctctaa gctaatagta 84840attagccaga aggaagggaa aactgatagt taaaatgttc aaaagatttc tcacattcct 84900atcatagttc

tccttctaag ggtgaccacg taagcaggca gggacatgtg actaagtaga 84960gcagcatcca acccccacct tgcacggtca cacacatact gctccattga caccatagtg 85020tcttggtgtg agctcttcat tacttgactc aatatcttct tcctcatctt ctcagctggg 85080gttgttgggt atatcttcat tgcagatatt agcatccttt gtggtcttct ttgtctttct 85140attctagggc cagcacagtg ggaggcctag tcaactgagc caaactggat ataaccacaa 85200ggtcaaaggc aggagccagt gaggagatct tggttttgag gtcattcctg gtgcgataat 85260aaccatcctg tagcattttc ttgtcactta gagaaggcat tagcaaactt tttttgtaat 85320ggtcttaata gtaaatattt ttgactttgt aggctatata gctactcacc tctgctttta 85380tagtacaaaa gcagccatag acaattcata aataaatgaa catgttccaa taaaagcaat 85440aaaaacaggc agcagtctga agtttgtcga ctcctgattt ggaatcattc cagaaagtga 85500aataaaagca tggcttcttt tttttttttg agacaaggtc ctgctctgtc acccaggctg 85560gagtacagtg gtgtcatcat agctcactac agctttgacc tgctgggctc aagtaatcct 85620cccacctcag cctcctgagt gtctaggatt acaggcatgt gacatcacac ctggctgatt 85680tttaaatttt ttgtattgat ggggtcttgc tatgttgcca aggctcacct caaactcctg 85740gtctcaagtg attctcctgc cccaggattc ccaaagtgct ggaattaaag gtgggggcca 85800ctgtgcccag ccaaagcatg gcctttctaa gggtgactca ctgtagcacc tcctgagtac 85860tttcctatca agtatcctgg accacttttt aaataattca ttctaaaatc catatttagg 85920attgattcca aatttgccaa cctgtatttc ccaaataact ggcatgataa ttcttgtctt 85980tttcccaaat gctcattttc cactcttcaa acgttgagtg ttgactgaag ttctgtggtc 86040atgtttacag tcatttttat gctctttgta ttgtacatat ggaatgtatt taccatttct 86100gttagcaatg atttcttgca aaaacaataa cacttgctag ttttgcgtgc ttaaaaatat 86160cgagccctgg cgctctctac atattatcta atgtaatcct tatattaacc ctgtgagtag 86220tcattatcac ttcttttaca caggaggaag ttagagaaga gtgttaagtg ttcttttagt 86280cttttccact ttgtctttag ttttctctta gctgttcttt taaattctaa ggtcattctt 86340atctaaaaac ttaaaagagt tgatcagcct ttttatcaag tgttaaattt ataccatctt 86400ttttctttga acagggctgg caaataaacc tggatttatc ccttagccct gttacagcaa 86460gtctcagaaa atttggactt cagcttcccc agtgatacat tttcaaatgc ctatgtatgg 86520attgcccatt agtttattgg ctagaactaa aggaaatcag gcaagagaca aaggacattt 86580tctctagggt gtcagtcaat gcaaaatgtt aggactagca tcagattttt ttttttttac 86640aaatgaaaat aattgaagtg tggtagaagt tcctctagtt ctggcagtcc taaatattgt 86700taactgaaga atgatggggc tcataaattt ggaaaggaga gagaggggaa aagagaacgg 86760gaatttatgc tgagcagggt ggctaagtat atatattcaa caggctatag gaggagctat 86820tagtattcac gaaggggtgg cacacacata catagtaggc taacgtgtat gcagcatgca 86880tcacaagtca ctttggggtg gagccttaac atttaatgta ttacagttag ggcctataca 86940tcaaaaggtg aagcagagga cacgaaagcc ctctgtgttc agcctctgta gactggccag 87000aaccactctg tggtcagagg tctcttatca ggaaagaatt cttgttgttg tgttgaaact 87060gcaaaaggga ggggcagtgt caggcaggtg gttgatacca gtctttcaga agcactggtt 87120tctgtttaac ttttagagaa gaaagcttaa ttggagtgtt actggaaagg gataccagtc 87180tagaccacaa gagaggattc ttggatctca cacaagaaag aattcagggt gagtccacag 87240agtaagatca aatcaagttt attagagaag tagagaaaga aaagaatggc tgctccataa 87300gcagagcagc actgaaggct tctggttggc tatttttatg gttatttctt gattatatgc 87360taagcaaggg gtggattatt catgaatttt cctggaaagg ggtggggaat tcccagaact 87420gagggtttct ctttctttta gaccatatag ggtaagttct ggatgttgcc atggcatttg 87480taaactgcca tggcactggt gggaatgtct tttagcatgc taatgcatta taaatagcct 87540aagataagct gtgaggatga ccagaggtca atttcctcac catcttagtt ttggctggct 87600tctttactgc ttcctgtttt ttcagtgggt tctttgtgac ctgtatctgt cttgtaatgt 87660cctatctcat cctgtaacta agaatgcctg acctcttagg aatggagcac aggtggtctc 87720agctcatttt atctatcccc tattcaagat ggagttgctc tggtttaaat agttctgaca 87780tattttcccc aataccccca aagggaccct taatcccaaa atttgcagac agatgaagat 87840ccatcttctg tagcttcttc tggctgaata caggtgatga tatttttgcg taactattca 87900gggtagagag gagctcagtg agaaagcatc agtatggtga aggccattcc taactcccga 87960gttctcacaa aaggtgatat ctggaagatt aataagtgtt caatttaaga aaacgttgag 88020tagtcttatc ctgcattgct acacaaagag taccacagca atatattcta caacagtaaa 88080gcaaaataag tataattatc ccaactaaac taaataacaa gcctttccat gaactaggca 88140gttgttggaa ccaagcttat atggggttgc tagccaattc caacacatgt tcagaattaa 88200aatactgatc cagatattta tgttaccctt ctgtttcttc tgagcagcag ctagagatca 88260ctggttggtt cataggaaca aacagggtca atctaaatgg cagaaaaaac tcgaaacaat 88320gaatgggact agagttgaat aacaagtata ccatagtttc tgaaacataa tttttctctc 88380tccagtctcc catttctatt gaaaacaaat catggtagga ctgatttgtt tgcacagtaa 88440gctttagtct tattatgctt ggcctggtta tttgtataaa gcatagcaat aataattatt 88500tgccacgtag gctttttaaa aattgacttt gatgtaactt tgttccataa gaaatctcag 88560attagacttt ctaaagcctt gagctgagac acagatttat ctgtgcctgc aaatacttgt 88620atgagttgtg tgaattctcc ttttgagatc ccaagataac tggagctcct aggcctgtca 88680gaaagtgaca ttctttactt accacaggtc aggaaccctg taaaggaatt gaatagacaa 88740ggtatgaggc cagcttttcc cagaggcttt catcagttct gtaagtcaac tttgattcct 88800taaagcaatc tgtttatatt tgaaagaatg ccattccagt caaagccctg gtaaaacagg 88860cagtgtctct aattgtgtcc tgttacaaag gaaaacagat ttttattgca catatgcaaa 88920ttactatgct gccataagtt aagaatactc acaaatagtt ttcaaattct tgagaaatca 88980ggtagaaaga aatatgctcc aaagttttct cataggagta taatttactc aatttttaac 89040aactgtaaat agctcaaaaa aaaaggtttc ttgactctga aaaatgaaac aaaggatcag 89100caacatttta agcaaaaagt cactagaagg ttattttgtt cttttattag tttagtccat 89160gctgttaatt cctgtttgct caatatttat gaacatattg gtttcccaag ggagactctt 89220gaaagttttt ttcctctcta tcttaatggc acactttaca aaatttttca gaaacctgca 89280tttaagagcc ctctatctga ttataaacca tcttttaaag aggatcaaaa caagacaaca 89340attttctgtg gataacataa agtcttagga aagccgtggt taaagacaca attgactaga 89400aattttggtt acttctgtgg catacaacaa ttttacataa cagttataat tattactgat 89460aacataaact aagtcatatc agaatttagg agtttcccat aattttggag cacataccaa 89520taacatattt atacaaatac aactcaaaga aagctaaaca ccatttcata tttgacagtg 89580cttcctgtat gattttaata taccaagtaa gccaaatatg tcatttttgg acttaagggg 89640acctcatatc taaagtattg accagatcag gaaaaggcat aatatagaat ttgattttgg 89700aaagtttgtc aaatatcaaa gatttaaaac acttgatatt ataaaatcga atcccaggtc 89760actgtaaagt catttattta gccaaaatga taatacaaag attttccaaa agcaaaatcc 89820tttttttttt tttttttttt tgagacgagt ctggctctgt cgcccagctg gagttcagtg 89880gcgccatctc ggctcactgc aagctccgtc tcccgggttc acaccattct cctgcctcag 89940cctccggggt agctgggact acaggcaccc gccactacgc ttggctaatt tttttgtgtt 90000tttagtagag acggggtttc accatgttag ccaggatggt ctccatcttc tgacctcgtg 90060atccacccgc ctcagcctcc caaagtgctg gtattacagg cgtgagccac tgcgcccagc 90120aagcaaaatc ctttactcat tgatagaggg aagacagctt tccaaacaat gtctcacttt 90180ttcttcttta ttttgttgtt tattcaaaag gcaaacaaaa atcttccatg atcttttaat 90240attacatgaa aattttgttc aagagagaaa gccaaatttc atctttgcat taatgaatgt 90300caaatccaat tcttaagaaa accttgtaga caaattattc aatcttaatc aattttacca 90360tgagataaga ttctcataaa ccttttgtag tcctttacaa tttttttttg ttgttgttaa 90420agagcagatt aatgctctaa gaaaaccctg ttgtgctttt attccaatgt tctatttatg 90480gaaaaactga ataataccct ttaactttag ctaatatttt aacacacaga atttctttta 90540caagattaat tttcactgac ctcccacaac ttactcaaac ctttagcttt atcctatgta 90600acttaaaaca gtcttttaac tctgtaaact aggcaataag accacattcc catgccttct 90660tataatcttt taccaaaaac acattctatt ttccttacac gccttgcagg taacactgtt 90720tctctggtag cctcaattac atgtgctaca atgttaactc ttagcaactt ttatatttgg 90780tgaaaagtct gataaataag tggttttaat tatgtaccag gtgtggagcc taggacgcca 90840gacagaagtg cagataaggt ctgagtcttt ccagcatagc tagggggcat ggccaactcc 90900acatgtcccc aggccctacc tagaatctaa tggctccaaa gcaggtgagt tgaacaatta 90960tcaagttaaa gaagcagttt atggcattga agcattcagc aaatctaatt taatctgacc 91020taatttagac cagatgtcta aattttgaag acatttttat tttaccaata tatttgattc 91080tctttatttc ccaaagatta ttaaagtccc atgaattaaa aggtgttaaa gtttttattt 91140ttctgacaaa atattcaatt taagtgctta tttttcaagc caattaatta gagctctttt 91200ctatgcatat cacacataca acacacaaaa atacacagac agaagaccca gtagctgtta 91260attttttcat ttgccagctt ttaagaatct taattggatt actggcttca gggtggagca 91320acgtgtgggg acagagccgg gaaaacatgc agtttctggg gcctaataaa caggtgcagt 91380tagaaggcaa aacagattcc ccaaaattac agatctcatt tttatattgg attctggatc 91440ccaaaaagag ggaatcagcc catcccctct gggagttttg gaaggtgtag aagaatgttt 91500ccataccttc taggtggcca agagcatgct tctctgatcc aaacgtgcac agagtggggt 91560attcccctat aactgctatt agccttccct taaagcatat ttcctgccta gttattacac 91620accaaggtta aaagctctcc cataatgcaa agtaatttct gataccccta caagtaaaaa 91680acattaggta acacaatgca aatcagagca atgccttgga ttttgagagg gatttgcttg 91740ccttcaattc ctggggttcc atgaggaaaa cagatttttc ccaaaatgga gcctgtggtg 91800ctccctcagt tttttctaag gaagcccagg ctgttagaaa tgatcttagg tcctctcaat 91860gtgggcatca agagtggcaa gaaaacaaaa tgagaaaaac aattcagttg actgagaaga 91920aaaaactttt atctagaaaa aaatcaatat aaaacctgcc agatagatag atagatagat 91980aatcttggac atcactttta attaagctga cttttaacca aatctcttat tatcagactc 92040tagccaggac aaacagctaa tatttctggc ttttgaactt taccaaaagt aacctcccag 92100gtgaaaccaa taagccttaa ctaaggttat gatttaacca caggtgtggg aggtattttc 92160aaagaggtgg taagcagttt ttacaagatc tggaacctcc aaacatagct cagagaaagg 92220aagattcaag acagggagtc agaagttgtt catgagggga agataattaa taaatggcaa 92280aggtcacata gatatcaaac cagaaaggac tcattcccga agctaggaat tgaatccagg 92340ccaccactgt gaaatagcaa agccttagtt actgagctgc agtactgcac agtctccatt 92400gctcctccga gaaggagcct agagcagcca attttgagct tgcaaaggct tttaactgct 92460caagataatt tttaggacta attgacagga accccaaaat tcacaccctc tggatggcag 92520agatcaggag aaagtacccc cacgtggtta caaggtcaag ctttcaagga cataaaacaa 92580gacgagaggg aaacttcatc cagtttttgt ttcagggacc tgcagaaaag tttgtaactg 92640accagtttgc gggccagctt gaagaccaga tttgtaggat tcctaggcct gcattctatc 92700ctgtggctag ctagggctgc cataatagaa tattacagac taggcagctt caaccacagg 92760tgtttatttt ctcactgctc caaagtctag aagtccaaga tgagggtgcc tgtaaagctg 92820atttctggta agagctctcc tggcttgtag atggccacct tctccctatg tcctctctgg 92880gcctttcctc tatctggcca agggagctat ctctggtgtc ttttcctctt cttataagga 92940cagcaggcct atggattaag gcctcacttt catgtcttca tttaagttta attacctctt 93000taaaggcccg atgtccaaat acagtcacac cgtgggttag gatttcaaca taggaatttt 93060agggacacaa ttcaacccat aataggaggg cattggaagg agagtgttcc aggcagagga 93120agtagtgcag tagagcatat ggaagtagga aagtgaggag caatggaagg ggttcagtat 93180ggtttgagcg tggggtgtgt agagggtgaa ggctatttca cccagtgcag taagctctat 93240catccacacc ggggttttac agtgggagaa aggagggtgt ttatttgcag gtcaagaagc 93300aaacagaatc agggagctca tgcttaagac ctgaactcca cagtggctta catgtaaggt 93360gcagaggtta caggcaaagg catcaatcaa cacatggaag ccatatattg gtttggccta 93420aaaaggtggg atatcctgaa gtaggggctt acaggttaca ggtaaatcca aatattttct 93480gatttgcaca ttgtttaagg aaggggatat ttgtctaaag atgggatcag caggccaggt 93540gtggtggctc atgcttgtaa cctcagcact ttgaaaggct gaagaaggag ggtaacttga 93600ggccaggatt tcaagaccag cctagtcaac atggcaagac tctgtctcta aaaaaaataa 93660aaaagaaaaa aagaaaaaga aaaaaaataa agatggaatc agcagaaagg aatgttaggt 93720ctggcccatg ggcggacttc ctccagactt ctcagaaaga aatttaagac aaagaatggt 93780gccaggcgtg gtagttcacg cctgtaatcc cagcactttg ggaggctgag gagggtggat 93840cacttgaggt cagggatttg agaccagcct ggccaacatg gtgaaacccc atctctacta 93900aaaatacaaa aactagccgg gtgtggtggt gcacgcctgt aatcccagct cctcaggagg 93960ctgaggcagg agaatcgctt gaacctggga ggtggaggtt gcagtgagcc aagattgcgc 94020cactgcactc caccctgggc aagagagcga gacttgagac tccatctaaa aaaacaaaat 94080ggaaaacaaa gaatggtgat aattcagtcc tcaattcctt ttcttttttt tttctttctt 94140tttttttttt tttaactgct cctgcggagc agggctacct catagccagt atgtccagag 94200ttgtctcagt tccctcgtta tctgtggtct ggaggatcca tatgatggtg atccaggttc 94260tgaaaaacaa ctctggaaca tctgttaaga tgttatcttt agtttctata ggaaaccaaa 94320catcttctga ctctgacctc cttggtgatt attttaagct actgtttccc tttttgctta 94380tcgagttgct catttacttc tcaaggctag caggatgact ggactttctc ttgaaggaac 94440tcaagctgtt cctttatttt tatgctcagg ggcggggggc actcagcagg tccctaagag 94500gtatccccgc tgtgtctcac tatgggtgaa ggctcagcgg gaagaaagct agataccagt 94560tggaactctc ttaaagtaag gagatcttgg gtactttatt aatatttttt tcaagctttg 94620gtaaagtatg aaataactct ggattaagag gagaagaact agaacttaat aaccatgaca 94680tttgggcaaa ttgtttgaag cctcagtttc ctcaacctaa aaataggaat tataactttt 94740tgaattgttc tgttgtatga gataatgaca gtgaaatatt ttggagccaa aaagcaatgc 94800atactattgg gggttattat tattttttga tctttcagca agccagctat agtagctttt 94860cctatataaa cacagtatga attcagtgcc ctcgctttcc tgaccctcac agcattcaag 94920ccctgtatgg accgctgagc tctcccttga agcacccctt agtccagtat tctttactat 94980tttccccttt aacaatttaa acttctttca aaacaactgg cagtagtttt ttaaaaaaga 95040aaacaggcta ctcttcaaat taaaaaaaaa attgtcttgc tttaggaaaa atgttcttct 95100gtcttttcca attatcttat ttcttctgcc tctcatctgc cttgcctagg cagaattatt 95160ctcaagcctg cacatgctgc tgtgcctctc tggcttctag gccaaaacat aggctaatag 95220tactcttctc agctcactga gctctttcct gccgtcattc aaatcacctc tgaaatcctg 95280ccttttgata aagtaatttc tgactgatca gaggaaagtg atgattttct ctgtgacatg 95340tctttttatt ttccatcaca ctcagtgtct tgtccttcta tgcaacatat ccatgtattt 95400aaaaaccctt gtatatgtat ttgccatgta tttgtgaggt atagctcgtg aagtaaaaaa 95460agtctttatt tttttaaaca catcatcatt tcagcttcaa agtcaatgtg gtctcttgag 95520aagttaaata tgctgcattt gaaattttat gtttctcatt tttcatgttt ttttttaaag 95580ccccttttaa ttcctcatgt atttgaatat tccaggaagc tagtagagta aaaagccaaa 95640gtgttaaagt gtttataagg aatgtgactc atcgaaattg actcacacaa ttcatcagct 95700attgtcatcc atatgttctc attatttatg tggcttttgc tttatttaat cagatgactg 95760aacttatcat cgtgggattt tgcttgtagt tgtttaatat tatataataa aatactcttg 95820tgtgaaacaa gttaattgac tttttttaat taaaaaaaat ttatgtgaga gtcaggagtt 95880acatgtgcaa gtttgttaca tgggtatatg ttgtgataca aagattttag cttctaagga 95940tctcattgcc caagtagtga acgtagtaca ctataggtag tatttctaaa cacttttccc 96000ctccccctct tttggaatcc ctagtgttta ttgttcccat ctttgtgtct atatgtacct 96060aatgcttagc tctcacttat aagtgcggac gtgtgatatt ttggttttct gtttctgtgt 96120taattcattt aggatagaga gactccagct gcagctgtgt tgctacaaat gacatgagtt 96180cattcttttt tatggctgca tagtattcca tggtttatat gtatcacatt ttctttattc 96240agtccaccat tgatggtcac ctgggttgat tccatgtctt tgttgttgtg gacagggctg 96300tgataaacat atgagtgcag ttaccttttt ttgtataaca gttcataata aaatactctt 96360aacagtagca cagaatttag attgcttttc aggctagaag ggataattga aacatagaaa 96420aaaataatga ctcctaagca tagaaacaga cccaatcata aagctctctt cctctctttc 96480tgcctagtgt tagatcttat tcattgtctt aaagcactgt gaccattttc agtgaaatca 96540cagttttatt catgaaaaga caatgaattg gtgtaagtaa tcatttgagg atgaaggtga 96600ctagtctgtg atcaacacca gtacttgaag tacttgtaaa acatgaattg accttggtta 96660aattgcagaa aataaagtat tagtatacat aaacacattt tctctcagca ttgaaaagtt 96720atagtctata atttacctgc ttgctaagaa taaaaatatt acttagaggt ttatcaagac 96780cttttttcta caaatggatt taatgtacag aattattcca ttttctatct gtgctctgta 96840tactaccacc tagtggaata aaatgcaaat ttacctgtca aaatcaggag aagaaaatga 96900accaggggaa atttatttca ggaaaaaatt ttcataacac gttattgtta cttcttttag 96960tataatgtag tttgcataaa atacattagt ttggagtgaa aaaagtccca gccatttttg 97020tgatagctat taaaatgcta ttagtttgtc cacaaataag ctattctatt cagaaactta 97080gaagctaggt aaattattga gatgatgcca gcatattata tctctaaatt atgttaagaa 97140gcttctctaa attcctcatc actagggtgt attagtccat tttcacactg ctataaagaa 97200ctacctgaga ctgggtaatt tatgaagaaa agaggtttaa ttgactcaca gttctgcagg 97260cttaacagga agcatgactg ggagacctca ggaaacatac agtggaagaa ggtgaaaggg 97320aagcaaggac cttctcatgg cagcaggaga gggagagcac aggggaagtg ccacacactt 97380ttaaaccatc agatctcagg agaactcact cactctcaca agcacagcag ggaggaaatt 97440cacccccacg atcctatcat ctcacactgg gcccctcctc caatttgaca tgagatatgg 97500gcagggacac aaatccaaac cgtatcatag gatttgttaa aaaaatctaa catgttctgc 97560ttcaaggcac ccatgaaatg aaggtgtcat ttcttaactg agaggttaaa taaaagtgca 97620gagataagat ggttaagttt tatcgtagct gggaagaaaa gcgggtgtgt gtattatgct 97680taggtttttc ctcccaaaca atgaaaccca aaaaggcaaa tgaagcttta aggcgcttta 97740tcctttactg gtaggatggt cctcctttaa tcttcagtct ctgttaaaga acaaacacaa 97800gctaacaatc aaaacctgtt gttgcttgct gacggatttc tctaacatag tcttccatca 97860accatcatag gtttgttgtg gccacccagg ccctttggtc gtcatgttcc catggaatgc 97920taatgaaatt accttcccat ttcctaaggt gacatgcctt tcagatggca ttggtgtgtg 97980cttgtgtaaa cacatttttt tgtgctcatg aatattttac ctgcctgatt ttggtgatct 98040gagtgttgag cagtgggtga gggatggtgg ggcaatgggt agtaagggga agtttaattg 98100aagttcagat aaaaatatcc ctccagaaac attacaaagc cacaaaatca gctgaagttg 98160agtcttctat tgtaaagatt ctctttcttc tcctgacaga tccccattcc tatccaggta 98220gaccaggctc tagtgaagat tggacacaag tggtttatat cccgaagctc ttaacctaag 98280agtcctgcct tgttttttta cttcatgtgg tcttatattg ctgaggatag cccagtgatc 98340atttctacct taatatgtag ccttcaaaac gttgggtctc tcagttttct tccttaataa 98400acaatgaacc ctaattattt ataactgctc ttgtgatgga ggaattggca tgattttgca 98460ttgtgggctt ctggctttac agtgtttgtg ggaaagatgg tcttctatct ttgttattta 98520taagtcattc attccctgtt tttttgaaga tattgttaaa taaaaaaact tcagctgaat 98580taaatttaaa agtttttaat tgagcaaaga accattctca attcgggcag ccttcccatc 98640cagagtagtc cctgtgactt cagtgcagcc acatggtgga agaggattta tggacagagg 98700aaggaaagtg acatacagga aacagaaaag agattcagaa acagctgaat tggttataac 98760tcagcgtttg ccttatttga acatggtttg aacagttggc cacgtttgat tggccaaaac 98820tcagtaattg gcacaagagt aggctaccat ctgtttataa tgtccactta ggttatagtt 98880catgatgtgc aaagaaacct ttaagctgag cttaaaatgt aatgaggcag ctgtaggcta 98940aacttgattt aacagtactt atccctctgt tgaaattgca ctcttgctac ctgctagttg 99000atgtgggcag gtgtgctaat gacacattcg cctgcaccta ccacctgctg aagaccctgc 99060catgtcctga agcagtcact taggctatga aacagaagga tgagttagag aagtaaatat 99120tatattttac cccccaaagc ctaaaaccat gtctaggttc tcccctttct caattcccaa 99180tcatgcaacc ttgaaaggtg ttatatagat agttgttaga aatatgtctg tcctccaaaa 99240ccctactaac acgcaaaaat ggacaaatct agcttttttg ctaaaatcct aacaactcag 99300aaagcaaagc aaaatgaaat gtatgtactc cattctcagg atttccttct taaaaaccac 99360taggctttgt gtaactcaat tttaaaagta tggtaatagc tcctgtaatt cgatggcttc 99420ttctgggaga cagatataaa tctattctag actttaagac tggtgtccac attttaagtt 99480acagttgtat gtacttctac tttgttgcag ccttctcttg gagtcaagaa gcctaccaaa 99540gccctgctct ttgtactctt gagcccagtg ggaccttatt tttcaagtgg aacctttaat 99600ccagtgtccc tgtgggccaa tcccaagtat gtaagagcct ggaaaggtgg aactggggac 99660tgcaagatgg gagggtaagt aaatctgtgt ctctgtctaa aggaaagaca ccttcatgac 99720catttagtta gtgccatttc acttcagtat gaacacatat aatacttttc aaactttaat 99780gctcattgtg tttcatggtt aattttcagt ttaatctttc agcaagccag ctgtagtagc 99840ttttcctata taaacgcagt atgaattcag tgccctcgct tttagatgtg ctagtttaaa 99900ggatagccca tggccctttg taagggagaa acactggata tgatatctag ggaagaactg 99960aagtaagaaa

ctacaacaag catcacatcg gtgctttgga taaacttccc ctgggcgctg 100020gtctctggct gcaggctgac ggctggcatt aaaaagcatc tggtcctggg acccaggctc 100080tcagttggct ccagggagtc atgtctgggg aaggtgcccg cttcactgaa gtgctgtctt 100140cattgccaca gattgtggcc acacctgctg ccaactggct gcgggacagc cctgctttgg 100200ctctgtcagg ccagtctcat aggccatatg tagctggcag gaaataaaag agcatttgaa 100260aagtgttgga cgatttcagg ggtggacttg gccatgagtt gggaatgccc ctatgggtga 100320acgagaataa ctggtttaag cagcatgggt tcttgctttg catgtatcaa atggtgctgt 100380ttgcatactc agggcagcag ctgtcctaga aggtgactcc atggcagtct tgtgggccct 100440ggtaggacat ttaggtccag gaggcagggg agagtcacat gacgtgctgc tggggtatta 100500gaggcaatga ccactggctt tgacccctct gtagtcttgc tgtatttcct ttttcttttc 100560tctcctcacc tacccaaatt aaaaaagaac ggttataaaa gtcatcccca ctggcaactt 100620tagcaactgc attccctcaa tgggtagaga aatccaaatg gagtgcatta aaactaggaa 100680gtctattctc cttctggctt agagcacacc ttcctgtgtc ctaggctagc caggttgaaa 100740actccttttt ttgactcttg atttcttttt ttactggttc aaacttcttc gcagagcatg 100800tgcctatgta ccactgcata ccatatatat accatatata gagagtaaat aaacagtctt 100860gatgaaaagt aataaggaaa aagtttccct gtttaaaata ttgctttcta gctccccgac 100920ctgtttagga aaaagataac ctggggacac agaaattgca gggcaatctt tattaaccgg 100980tatttgggca ggttgtaatt tattttgtaa acaatgattt aatgcactat tgcagaatac 101040atgatcactg taggccagtt aaaaattaat gttttcagta ccacacagag tgaaccctaa 101100tgtaaactgt ggacttgtgg accacactaa tgcaagatga taataagaag aaaaactgag 101160agggtgttcg ggaaggggta taatagggga attctgttac cttttgctca atttctctgt 101220gaatctaaaa gtactctaaa ataataaaat ctattataaa aatatttgat tcattaggct 101280caggtggact atgatccatg gaaattgact tgaaatctct taggaaagga agagaccgga 101340gaagaaagta ttgaactcat aaattaaaaa tggcaagagg gaaggtggta accaaaagga 101400tgggcattta acctatatgc ctatcacttc caaaaagttc tagggccgtc tcctcctatg 101460cttctgacct ggagaggtac aaggggaaca aaatattccg catttaatat tatcctgttg 101520agttggcaaa gacatttgga gtcaacttta gttttgtgta ttattacatc tgtaaaccta 101580attaagtcaa cagttaccct tgacacctgt agtcaactgg tattattaaa taactattga 101640gtctcataaa gtcaagaact ttctgctttc tatctaagtg aatctagggc agagactgag 101700catcaggatt ctttagcatg cagccaagct tgagaagcac tgagctagag aaaggtcttg 101760cactgtagaa acagctttag ttccaggtga ttccttggtt aatttgggag gaataaggct 101820ttctgtcact ctctctctct ttctctcttt ttctctctct cttgcacatg cacacgtgca 101880cacacacaca caaattatct ctcttagttt tttctttttt ccttgcattc tgattctgca 101940tttaagagta caagctttga agtcagaaag acctggctta aaaacctaac tgtcataatg 102000gtgcgtaaat gtcgttatag atttgtccaa acccatagaa tgtacaccag gaatgaacac 102060taatgaaaac tctagacttc aggtgataat ggtatgtcaa tgtggttcat taatttcagc 102120aaatgtacca ctctggtgtg aggcattggt aatggtagaa actattcatt tggatgggga 102180gaaagggata tgggaaatct ttgtacttgc ctttcagttt tggtgggaac ctaaaactgc 102240tctgaaaaaa acctgaagtc tttaaaaaca aaccaaccta attgccttgg gcatgttact 102300taactgctct atgtatcagt ttcctcattt ttaaagttga ggcaataata ccttgcacag 102360attaagtgag ataatagaaa gtgcctagga tagtacttgg catatagaaa gctctcagca 102420aatgcagtat gataacctaa tggttaaaag cttgggttta ggagtcaaat gtctgggagt 102480tacacactta actatctgtg agatcttcta caactgaatc ctctctccaa gtcttccaat 102540gaacaataaa gtctagggtt gtttttagat gactcaatga aataatgtag ttaagtactt 102600agcacccagt ctggcaggta tgggttgcat atctcttatc tgaaatgctt gggaccagat 102660gtgttttgga tttcaaattt tggagtattt ctctttgggc atccctaatc caaaaaattc 102720gaaatccaaa ttgagcatca tgttggcacc gaaaaagttt tagattttag agcatttcaa 102780agttttaaat tagggatcct caacctgtag taaactctca cagtcactga tgttgtgagg 102840ttttctcact ttctcatttc atttcctgga ctctctttat cttagaagaa atcagttaaa 102900ttttacataa tagaatttat tcttttggag ggatgtattt aatatgtcta ttctcccaga 102960taacctattt aaaaccatat tgaaatgttt ctatgtcaac agctttctta ctttttcatt 103020tttctgtttc ctccaagaac atgtttctct tatgaatatt ggcagcacat gggcgggaac 103080ccaactatat taccatggta tcagttatcc tgtggacatt aataatacag cttacacctg 103140tgagagaact ctgggaaaat taaaacttgt ttgggggaat aaagaccatc tacagaatat 103200aataatacat caatcaatca attaaaactt aaacataaaa aacccttttc ttttcagtgc 103260attgaaatag tcactgtctt taatcctctt tccttgctca gtgcttcatg aagctgagga 103320gccatggttt taattcagct acactttcag aaatgtgtat gcatttgtat ttagaagctt 103380ctttgaaagg ctaaatattc atcctgtaag aattctctat gtgtttttta atacagtcta 103440aagggcattt tgtatatgaa aaaataattt attttcaggt agggtaaaac ttcactgctt 103500cactacttcg tagttgtgtc tacgaatgag aaaaaattca aataaaatag ttattattat 103560tagtttttag agatgcagtc ttgctgtgtt gcccaggctg gtctgggact tctggcctca 103620agccatcctc ctgcctcggt gtcctgagtc actgggatta caggcatgag ccaccacacc 103680ccactgaaat agttattttt taaaaaactt aatttcatta ggatgtaaca gtctcatgta 103740actcatcctt tggcttttat tgttattatt tattttttcc aagcaaccca atgagatata 103800taaagcagat atttttatct gccagataat taaatgaggg aaaaataagg actaacttgc 103860ttaagttcac atataccaaa tagtggaaat gcaagagctg tcctcaggtc tgttaacaac 103920aaacctgtgg tctttctacc agacgtcccc tgcaatctgg tttatactca ttattaaaaa 103980gcatttgtaa tttaactcag ttatctattt actatcagtt atgaataagg attatttgac 104040tttttatggt cattaaacaa tagcttccta tctgttgtct ttgtcttttt aatttttatt 104100tattttattg tttttttaat agcttcctat ctgtatacca gacttgcttc atctccacat 104160tgaccaagaa tttatatttt gtcatctgta tttagaagca tatgttttaa gcgtctttta 104220atggctcttt tttttttttt gctgggaggg gacagtctcg ctctgtctcc taggctggag 104280tgcagtggca ccatctcagc tcactgcaac ctccgcctcc ctggtgtgag tggtgctcct 104340gcctcagcct cccgagtagg tgggattaca ggcgtggtcc accaaaccca gctagttttt 104400tatatttttg gtagagacag ggtttcacca tgttagccag gctggtctgg aactcctgac 104460ctcaagtaac ttgcccacct cagcctccca aagtgctgag attacaggta tgagccactg 104520tgcctggccc ttttaaggac tctttttttt tttttttttt tttttgagac agtctcactc 104580tgtcgctcag actggagtgc agtggcgcga tctcggctca ctgcaagctc cacctcccgg 104640gttcacgcca ttctcctgcc tcagcctccc gagtagctgg gactacaggc gccagccacc 104700acgcccggat aatttttagt atttttagta gagacgaggt ttcaccgtgt tagccaggat 104760ggtctcaatc tcctgacctc atgatccggc cgtctcgcct cccaaagtgc tgggattaca 104820ggcgtgagcc accgcgcctg gcccttttaa ggactcttaa cattaccttg gtgtgagtca 104880acctcatcgt gctccaatgg caatcaccat agtatgatgt ctattttcca cagcttactg 104940gaatatttca gctattagtc aatattcttt cagttgcaag tcagaaaacc aacttgaaat 105000tattatttat ttatttattt atttttttga gacggaattt tgctcttgtt gcccaggctg 105060gagtgccatg gcacaatctc ggctcactgc aacctccgcc tcccgagttc aagcaattct 105120cctgcctcag cctccagagt agctgggatt acaggcatgg gccaccactc ccggctaatt 105180tttttgttat ttttagtaga gacggggttt ctccatgttg gtcaggatgg tctcaaactc 105240ccaacctcag gtgatctgcc cacctcagcc tcccaaagtg ctgggattac aggcatgagc 105300caccgtgccc ggcctggaaa tgatcttaag cagacaaggg cttatgaaac taggatgcta 105360ggggctaaag caattatttc caagtttctt gtgtcctttg cacatccccc tttttcttcc 105420cttcttcctc tgcctctggt cagagcttct ggctccatgt tggcctaggg ctctcccact 105480tcagccgctt tcttctgtga agtgtggtga tcatggacac agccgacccc agttttacag 105540cataccaagt aagcaacccc agaagggaga aaatgcctgt atttcaggtt atagacatta 105600aaatgagtga atgcacccaa aaaaggaatc atgtgactgt cttaggttat atgcccaccc 105660tttaactcag ctgcagcagg gcaagatgct atattgtcat cagttgtggt agggcaagat 105720gctatattat cagtccaagc agaatgacat agctctatag aaagactatg tttttataag 105780agtatggaat atagtgcaga tgaaaacagt agatatacac taacatgtgg ctctaatgtt 105840taatttttat tttttttgag acagagtctc actgtgtcac ccaggctgga gtgcagtggt 105900gctatcttgg ctcactgcaa cttttgcctc ccgagttaag atgattctcc tccctcagcc 105960tccctagcag ctgagattat aggcacccgc caccacgccc agctaattct tgtattttca 106020gtagagacat ggtttcacca tgttggccgg gctggtctcg aactcctgac ctcagtgatc 106080cgcccatctt aggctcctaa agtgctagga ttacagacat aagccaccgc gcctggcctc 106140atgctcaact tttatttaga caacagtaca aattgtaatt ttacccagat gtaaaagagt 106200ctaagagacc taaatagata ttttgtggta gattacatta atgtaatgta atgtaatgta 106260ggagttttac attactacat ttgtagttgt tttagttgtt tttcattgtt tgtttctgtg 106320tatttctggg gatttcatgg tgcaacagga ggactagagt ttattcccga tccctgactg 106380tcttacggca gtacttctca gacctactga gttatacaac caggggtgta gggaggcaag 106440cagtcatcac atttatttga ggactctcat gttttgtcta aaatattcat ccttatttta 106500taatatactc cataattttc ccatataagt ttagataaaa gatgatacct taaaagtatt 106560ataacactaa attgtcattc cgggaaaatg tgctgtgttc ctttcatttt aaataatctg 106620agatgaatgg tgcaggctga gaaaaatagg cttttgaaat actttttggt caacatcgag 106680acttttaaca tttgtcctat cttttagggg aatttagaca ttgggcatta tgtattcctt 106740ggatacatta aaaggtgtta gataagagcg ctcacacttg ctgctcttct attgcaactt 106800gacagaagtt acttctctaa accttagttt ctcatctgaa caatggaaat aatgatagtg 106860tctatctcat agtattggtg tgagatttaa atgaaataat tcatgtaaaa ttgcttggtg 106920tgtggaaaca tagtaacttt taactgttct cattaacttg gctatttacc tgtgttcttc 106980tatcattaca tttcaagtta aaatttcaag gtttcacgtt gttctctctc caatgaatgc 107040agttaaatca cttagatttt ctaatgagtt ttcctttaat gttatgcagt tgactagaga 107100gtgtatatat attaagaaca taataccttc actatgtcca catgtgaatt aagagcttga 107160ggctatcaga gggtagaaga tgagggagtg gggatgaagt atgtttgtaa cctgtgtatt 107220ttctctttct taaaggaatt acggctcatc tctttttgcc caatgtgaag cagtagataa 107280tgggtgtcag caggtcctgt ggctctatgg agaggaccat cagatcactg aagtgggaac 107340tatgaatctt tttctttact ggataaatga agatggaggt aatccactca gatttcactg 107400tgtgcatttc tcagtcattt tcaacaggac cagaaagaca agagctagaa acttagtaca 107460agggagtaag tagcacagtt ccaaaggcta agtaaggact actgtgcttt tgctgcccaa 107520atagacacaa gtttcttttt tttctttctt tcttttttaa agaggtggag tctcactatg 107580tcacccaggc tgcagtgcaa tggtgtgatc tcagctcact gcaccctggt tcaagcaatt 107640ctcctgcctc agcctcccga gtagctggga ttgcaggagc ctgccaccat gcccagctaa 107700tttttgtatt ttttttttta gtagagatag ggtttcacca tgttggtcag gctggtcttg 107760aactcctgac ctcaggtgat ccaccggcct tggcctccca aagtgctggg attacaggtg 107820tgagccactg cacccggccg agtttcgatt taaagaagct ctagaggttt tttgtttttc 107880gttttttgtt tttctggctc tagatgtact gattattgag atactgagat gtcacattaa 107940gggatttaag ttaccatgat tggaagattt gcttccttat cccttctgca gttccccaac 108000aattttccta tctgaacacc ttgcattgag acacaggtct cagatcaggt caatggtcat 108060tcaccatata ccgtatataa aatgctagag taataaatgc agtgtactga ttctactgga 108120aggattttgt gtactctctg gctgtaattg ttttaacaat tgttgccttt tctacatatt 108180ttgaaaatgt atcacaatct ctccaaattt actctagaac tcaatctgat taaagagcac 108240cattttaaaa gataaatcaa tgtatcttgg gattgtaact agatcctggt tcattcaaga 108300caatttcata tatccactat agatatcaat atttctctat tatctttaat atcctgagta 108360ctcattactt ttctttgctg ttttttttta ttagttggca gagaccatag gggttcagtg 108420aagtgttggc aacgtgtatg atattgaatt aaatggccaa cggtgggaga aaaacaggca 108480tttatttcta ttagaatttt gataatcata ccaaatttag aagcgtattt ttagacttgt 108540ttacattctt aggttgttca tttcacagta gtaattatag agactagaaa tataaatgat 108600gtttccaaat acttatgaag tctcagtgtt agtagtttca attaaatttt ttaaaatgca 108660gtttatattt gaaagtagct acagtagcct ctcttgctct aatgttattt ggctacaaaa 108720agaggaaaat ggtaatttag atgtggctga attcagagct aagtactaat tttagtgtta 108780gttgcagaga ctaacaagat gagtcttata ctgcagtcag aggtagaata aacagaagat 108840atggtgagta agccttgtcc tgggcttggc cattggtagt ccttggcata tgaaaaacca 108900gatacagatc attctcatcc ttccattcct gctgtttgta cttggcactg tttgaaaata 108960aaatttatac aggaatattt atgatttata aatttgagtt actgtatgtg acatataaca 109020aaagctacac ttggaagatt gtagccagtg ttgacctctg cacttagaag ataataggcc 109080gattcaaccc ttcttcccat ctgcccactc ttacccccac cccaaactcc accaaaaaac 109140cacacagctc aaaacaaaaa cagttacatc attcagaggt ggtaccatca ttatttttat 109200ggatgggaga tgtcagaatt taagtacact ctgaatcaga gctacatgat ttaaccagaa 109260acaccagaaa ctgtcctggt ggaaaattgt tctttatcca aacaataatc atgaaacatt 109320tccaccatgg cttttaaagg tcagaataga aatgagtgag tttgtcttct gcctcttgca 109380aaatatacaa gaccttaaga ctgttagtta ctattcagat tatggttgcc tgggataact 109440ttagttttaa tatactcctt cactttgggg atgttcatct aacagaacaa ataaaattca 109500gaataaggag aaaggaaata gaatatatat ttgaagtaaa tagaatgtta ggaaaaacct 109560ttgggctaaa aaaaaagaca tgcaattctg aagtaacttt gatttatatc atatgatttt 109620aagaaaatac aatgaacaaa cgagttgaaa atcagcacaa tactgatttt cacaaacgtt 109680accgatagga ggtataaaca gagttctttc ggtaatagcc tgccgtcttt tcatgagcgc 109740ccacacacac tgctcctgtt ggttgagatg gctggtgcag gaaggtggat ggggtggtgg 109800atagtgtgtg ttcaaagcac agtgctgtgc acagtcacta tgtgtggcac tcagcttgta 109860actcatggga gttttgattt cagtaacagc acccatggtg gcaagatcac acatcatcac 109920tctgttgatg agtaatttaa cccatacgct tgctattcac catttgaaca aagcattgta 109980tcatatcctg gaccctggag ataccctgaa aaataagacc caggccttgt ggttgagttc 110040acagtcactt tgggaaaaca accacagcag tgaatctcgg tattgctcag gccacatcat 110100gagtcttctc ggacacgtca ggcgtgtata cggactcgac ttggagcact cttcctcaga 110160tgtctgtacc gcttgctctt tgacatcctc caaatctttg cttacaaatc ccattctcag 110220tctggctttc cttgagctct taatcaaaat cataaactcc atttcccatt tctcctcagc 110280attccagcat tctccattgc ttttccttct ttgtttcccc ctgtgtagtc taacatacta 110340tcaacacaat aaatgtttac ctgtgtctat tagaaagtaa gcagggagat atgtcagttt 110400tgttcactgc tgtattcata gagcttaaaa cggtaaacag cactcaatat gtatttgtag 110460aataaatggc taattgtgct gatggtgttt agggcactta tgcagaccta cattcctggt 110520ttccattagt gtttgacttt gggaagtcac agatgaatcc tgctgttatt gcttctaaat 110580tcctcatctc ctaaaaatga cttctttgtc aaaaacaagc tgcatttgta ggttctgttt 110640tcctcatgtt gggcaatctg gagtgatttc tggctcttgt aagtatgttt gtggttgcag 110700aggaaaatga atatttctca cccaaatgtt gtcatgtcat catctctgtc tggcaaccag 110760agaagcagat gttctgttcc ttgacctcag gctagtggtt acagttctgg gtgttaaaca 110820tgtttcacaa aacagcactt gcacatgcgg ggctgctgtt ttcatttaac ttcatgtagt 110880ctcagggctc agcaagcttt aggaaaggtc cggtttgggg gcactggaag tgtgtgtgtg 110940tgtgtacata tatatacaca cacaaataga tccatacatt tatgtatcta gttggctagc 111000tattgcaaaa cacatgttta ttttgagatc atcaacactt ctaaacatga caaagagtag 111060ccctaagaac attgccaaga acaaattttc tcctttccag aaagcaattt tcagcagatg 111120attttcagaa acaaaattca aaaaagccat actgctgtat cctagcaaag ataacttatt 111180cgtttatttt ttactcaaaa acatttatta tatacactct gggctaggca caatgcccag 111240ttttgaggat agaaggatga agatagagtt tggtattcca gatagagctt gattgttggg 111300catgtctgat gtaaccccag tggagtgggc gagcctagaa ccaccatgta ttgagggaga 111360gggtggtggc ctcagtgtca ggactcacta gattcagact cctgggtgtc agaagtgggg 111420aggaaaggga gatgctgagt gccagagggt actgtaagga gagcttgtgc agctgatgga 111480tcatgcatga tgcctgtgaa caattgtcct actagacctc acagtagtta gggatgtctg 111540cagtcatctc acagtagagc agtagctcag ctttggagtt ttgtttcttg aatgtcttct 111600tttttaaccg tacacgtgct tgagctcact ctgataagcc cattacattt gaatctcaga 111660gagcaaaggc agcatctcca tacttgttgc tgatgctcca ccaggtttga aaatcactaa 111720agatagactc ttaggctggg tgcggtggct cacatctgta atctcagcac tttgggaggc 111780cgaagtgggc agatcatctg agctcaggag ttcgagacca gcctgaccaa catggtgaaa 111840ccccgtctct actaaaaata caaaaattag ccaggcgtgg tggcgcgtac ctgtaatccc 111900agctactcag gaggctgagg caggagaatc acttgaccct gggaggcaga gggtgcagtg 111960agctgagatg gtgccactgc actccagcct gggtaaccta aaaaaaaaaa aaaaaaaaaa 112020aaattagact ttccaagggc agcgtggaag cagtgaccag cctgagtagg cacgcacact 112080tcttggggat agcctcctcc atagcattct tagaaggttt ggtaatgacc agtttttctg 112140agtaagaccc tatctacatt attctaatta gtaaccacct ttcatctgct aaggtaaatt 112200ttcacttcag aatattcctc ttaagaccat gcaataactc ttactgtttg ttggtggaaa 112260accatctcat tattttactg gttaagggta aactgaagat gattagataa ctttccttcc 112320ttccctcccc ccttcctccc ttccttctct ttcttccttc ctttctccct ccctccctcc 112380ctctctcttt ctttccttct ctctttcttt tcttttcttt tttctttctt tctttctttt 112440ttctttcttc cttccttcgt tccttcctcc ctccctccct ctctctcttt ctttctttct 112500cttttctttc tttctttctt tctttctttc tttctttctt tctttctttc tctctttctt 112560ttctttcttt ctttctttct ctttctcttt ccttccttcc ttcctttctt tctctctctc 112620tccttccttc cttccttctt tccttccttc cttctttcct tccttccttc tttcttcttt 112680ttttaaataa gggtctacct gaagtgtgaa ctgatttggg aaatttgatc atgcagaaca 112740gtaaaatttt ctttatgttt gttgctagca aaattgtgat ggttttttaa aaaaatggct 112800attgataata aggcatgcct aatgtagtga aagtttgaaa atgtcccaat ttctgattga 112860cagaagaaga actggcaact cctccactag atggcatcat tcttccagga gtgacaaggc 112920ggtgcattct ggacctggca catcagtggg tgggtgcctt tgatatgaac aacttttgta 112980agcctgaaat aaaaaataat caaaataagc ccagcctagt gttgaaataa tatcctgtgg 113040ttccaaccaa tgttatctaa tctttaaatt ctaacgtgaa tgaaaagtat tcttctagaa 113100gggctttctt ggcaagacta ttaaaataag tattgttgat agcaagggca gagagaaacc 113160agtttagcaa gatgtcatag tggagaagta ttctagtagt agtctcagtc taccaggtat 113220ctcccaccaa cttttgtctg gttcatacct gatgtgcttc catccagaca ttccttaact 113280tcccaagtct gtgttgcttc caaatggcaa tgatacttct tcctttcctt tatttatacc 113340agtgtaacca tgcttgccgt agaaatgaaa taatttcact gacatataaa tgtttactaa 113400tataacatta ttggtttgac tgccttcttt ttctctctgt cctaccccca tcctccaaaa 113460ttcatataca tgcctatttt aaaatcagaa catgcaagca aatgtaaagt tgttttcagt 113520agactttcaa attcgtgtga cacaggcaag catattaaac aatttggtgg accgggtgca 113580gtggttcatg cctataattc tagcattttg ggaggccaag gcaggaggat cacttaagcc 113640caggaattcg agaccagcct gggcaacata gtgagacccc gaatctacaa aaaaatcaaa 113700aacattagct gaacatggtg gtacatgcct gtagtcccag ctacttggag gggctgaggt 113760gggaggatgg cataagatct ggaggtcaag gtcgcagtga gctatgatca agccactgca 113820ctacagcctg aatacagggt gagaccatgt ctctaaaagt aaattaaata aataaataaa 113880taaataaata aataaataaa taaataaaat aaaatttaaa aaggtttggt tttggaaatg 113940acgtaatgta ttcaagacaa attattgaat gaattgggtg tctggtaaag gttcttggat 114000ggaacttttg acccaggtgt taaaatggtc tccaaagaac atgaaaaggc tttgagctta 114060ctgtggtcaa agagtactag tagtaatagg acaaatgttt agaaacacac acgttatcta 114120ggagcatacc agcatggttt ctctggaaaa gactttcaaa atagatgaaa tgtgctataa 114180ataattctac aaaaccctga agtagacaag acccaactgc tacatgctgg ctggcgcatt 114240gggcatgaca tttacaaacc gttggtataa ttttcaaaca gcttgccctg tcctaaatat 114300gtttgcaatt ggaaagatat ttttgaagct cagtaatttt tgttttatta aagaaaaata 114360tcaaccaagt acagaaggtt cgacgacaag ttgcaagtgg aaatactttc ccacactaat 114420gatttgctag catgaaaaat aggttattat ggaggaaatt ttttcttgac ttcatagctg 114480taatttattt taaaagctat tttaaaacat gagacgtgaa atgccaagag gcatgtaggg 114540ggtcaccact atttgccaga taggggaaat tgtccaaaga taagtaaggg tgagcagagc 114600aaaaacaatt ctgcttattt acaaaagagt tttcttttct tttctttttc aggacacaga 114660actcagcttg ttttcaatta atttgcctga ttttctgcag ttcatttact tttgaacaac 114720ataattgcaa ttgtagactg agagaaattg aaactttcaa agagccatat ttctattgca 114780gatatatttt cctgctcttc caaatctact tacagcatga gttcttcttt taaatattca 114840aatattttga atattgccaa gagctttgat ttccattttt atctcttgtg ggtttataaa 114900ttaagaaaaa atactcatct tattttttta aacctctcta tttttattgc cctttattca 114960aataacttgt tgacaaactt tgaacttgaa ccactgaggt aaaagaacaa gaattaaaca 115020gatagtttaa

acacatagct taaaaggatc tttttcccat ttcctatcct tgagcaaaga 115080atatattcaa acactttggc agaagtcaat gaggttatac cactaattcc atgatgaaaa 115140tcaactgaat gtgatactga aagagaagga agagaattgt cactgtaaag tcaactgtta 115200gtcatattag gaaaaaaaat acatacaata caatttctca aataaagtcc aaatatacat 115260tcaacgttta aaaataatga gtatttcaga tatttgaact cagtctgttc tttattccat 115320aaaagatata ggtaagccgt gcacagtggc tcacaactat aatcccagca ctttggcact 115380ttgggaggct gaggtgggag gatcacatga gcccagcctg ggcaacatag ggagacccct 115440atctttacaa aataaaatat aaaatataaa acctagttgg gcatggcagc atacacctgt 115500agtcccaggt gctcaggaga ctgagacagg aggatcactt gggcctggga ggtcgaggct 115560gcaatgagcc aagattatgc cactgcattc cagcctgggt gacagggcaa gaccctgtct 115620taaaaaaaaa aaaaaaagaa agagacaaac gtagaaagag taccaaattt ggagccaatc 115680agatcagacc tgggttcaaa ttgagtttct gtcacttact tcctttgtgg ccctggagat 115740gcccttcaac ctccttgaac cttagtttcc tcatctgtaa aatggggatg atagtactca 115800cccttaaaat tacagaactt ggcataatag cgggtgcttg ataaatggta gctataatta 115860ttaatattat ataatacatt gttctccttt atggtaaagt aggttttaag acactgattt 115920ttttgttttg ttttgttttt ggagacagag tctcactccg tcacccaggc tggactgcag 115980tgacgtgatc ttggttcact gcaacctctg cctcctgagt tcaagcgatt ctcctgcctc 116040agcctcctga gtagctggga ttacaggcac ccgccaccat gcctggctaa tttttgtatt 116100tttagtagag acagggtttt accaggttgg ccaggctggt ctcaaactcc tgacctcaag 116160taatctgcct gcctcagcct ccccaaatgc agagattaca ggcatgagcc accgtgcccg 116220gcctaagaca ctgttaacac ggagcatgca tcaagcagca tttgggatgc atcaattttg 116280tgagacttta tacaagttaa caaataagaa ggcaaaaaag aaggcatatg ttaaagtata 116340ccatgtgtct tgtggtgata atcttatatt ttatattctg ataatctcat atataaatct 116400gtgaccttga agtaggttac ttaacacctc gatgtgttca ccagtaagat ggtgtgccac 116460ttccagcttt cccttaaagg atgattgtga ccttgtctaa gtgcaatcag aatgttaagc 116520agaacagtaa gtattgcaat tgttttgcat gccttttcct ttaaaatata cttgttattt 116580tttatattcc atgcagggtg aatttaaggt gtcagagaga tacctcacca tggatgactt 116640gacaacagcc ctggagggga acagagtgag agagatgttt ggctctggta cagcctgtgt 116700tgtttgccca gtttctgata tactgtacaa aggcgaggta cgacaagtat ttcctcattt 116760cctatcattt ccaatcacat taaattacat ttaatttaag tgtatgaata aaattgtatc 116820tggacccaga cccaagatgc aaaagttttg tcgttgttgt tgtttttctt tattttaaag 116880agatggagtc tcgctgtgtt gcccaggctg gagtgcagtg gctattcact ggtgtgatca 116940tagctcactg cagcctcaaa ctcctgggct cacgcaatcc ttctgcttca gcctcctgag 117000ttgctgggat tacaggagtg cgccaccgca ccatgctagg tcttttttgt tgttgttttt 117060gttttttaac ttggcactac aaaaaaaata actgggacag tttatccaga tgaaactgta 117120ttagcatata tctactatgt ttccagtgat ttcatgtaag cttaaacatg gtgggaagtt 117180agttttgtcc ttggacacgt gtaagatctg tcttacctac atgtcgggat tggagctatg 117240ccgacagtct tctactcttc tctcttcctt cctaccagct cactagggaa ggctctatag 117300gtagttacat ttcagtttct ggttaaccaa aagtacttcc aaaccactgg attaggaatg 117360gcaaatagtt atggaaaatg cattcgagtg gtcaatccct tgattttttt ttactattaa 117420tgctgttatc attaatagta agtagaccac tttacaagaa ttattcattg gcaaacctgg 117480tgcatttact aaaatcttac aaaaggaatt tgaggatttg gttggaagaa atgttctcct 117540cttagtaaat tagtctgatt ttatatgtgc catacttttg ttttcttgtc aaattgtttt 117600gcttttcact ttataacaaa gctccaatac ttatgattaa cattggcatc taactttata 117660acttaaaggc atgtaagtat tagtcttata atgtgaactg gcttaagtta ttcatattat 117720agcagatcct tgaacaacac agggattagg ggtgtcaacc cccatgcagt tgaaaaatcc 117780acatacaact ttttttgttt gtttgttttt ttaaacgggg tctttctctg tcacctgtac 117840tggagtgcag gggcacaatc tcggctcact gcaacctccg cctcccaagc tcaagcgatc 117900ctctcacctc agtctcccaa gtagctggga ccacaggtgt gcaccaccac acccagctaa 117960ttttagtatt ttttgtagag acggggtttc aagatgtttc acaggctggt ctcaaactct 118020tgagttcaag tgattcacct gccttgacct cccaaagtgc tggtattaca ggcgtgagtc 118080accatgcccg gcccacatat aacttttgac ttcccaaaaa cttaactact agtagcctgc 118140tgttcaccgg aagccttatc aacaacaaaa acagtcgatt ggcacatatt ttgtatgtta 118200tgtatgttat atatgtattc ttacaataaa gtaagttacg aaaatcatgg ggaagggaaa 118260atatatttac tattcattac atggaagtgg atcatcataa aggtcttcat cctcattgtc 118320catcatgttg agtaggctga ggaggaggag gaggaggagg gattggtctt gctgttttag 118380gagtggcaga ggcagaagaa agtccacgta taagtgaact tgtgtagttc aaacccgtgt 118440tgttcaagtg tcaaccgtaa atgcaaactc cactggtttt caaattttac tttagagtta 118500ttttccctca gctgattgga gttttgctca actcctctga ctttaataat ggctgcttca 118560tttgttgagg ttttagaact tgcttttaag ggattgctct tgacataatt gcatcaacag 118620atagactgtt tcatgggaga agaattgttc tgtttcatgt caatacttac attgataaga 118680atgcatcaag gtaatgtgat ccatccactg aagttgtcat taggccagat tttttttaag 118740ttgaattatt atttcacttc tagaaataag aagtttataa agtttagcat aattttaatg 118800atccaggctt aggaagcatt tacagccaaa aagtaagtat atataattat catattatac 118860taaagggtat aatatgaaaa gtgtttgaga gcacagacta tctcctaaaa tcaaactatc 118920aaaacctgca agccagcaag gcatgagtag gcatgactca gatacaaatt agaagcatga 118980aatctctttc agccatgcat ttaatcatgc tatccaatat tgtggaggta gtggcccctg 119040gaagtttacc ttgggccaga gataggtata gaagcccctt ttatgaagtc atagacttgc 119100tttaatttat gctcccagaa tgacttgcat taaactgtgg caaaatatct ttgagttctc 119160atattagcca gagggttaat atgtagaaga caatcattca tccttacaga ttctcagaat 119220cttggaagag gtagggttct ttaagtttag ccactatttt aggtaactgt agctcctcct 119280tggttcttca aatgatcctg aaggctggta tacaaaccag ttatgcccta aaattaattg 119340gtaggtaggc aatgtataac ctgtcattgg ctagttttta ttcaaatttt ggatatgaaa 119400gtctttggca taaggtgcta gcactcagag tcagtaggtt ttagtgctat tccttaactt 119460cagtggaatt gccttagtat agcagaattg cttgagtgtc ttatctgtta tcaccatata 119520catgagtacc ctcaaattat ctcatttccc tttcttttgt agacaataca cattccaact 119580atggagaatg gtcctaagct ggcaagccgc atcttgagca aattaactga tatccaggta 119640aagcttttct tttcttttct tttctttcct tttcttttct tttttttatg tcaccttatt 119700tctgtcagag cttacaacta aattatattt caatgaagag gattaaataa tacaatttga 119760gatcaataag ttaaatttaa ggaagatatt cccaacacaa tgtgtgggca tgagcaaagc 119820agaaatggga aagaagatgt atgttttaaa aaaagaaaga aaatattgtt caggactcca 119880cattacttaa cattaaaaaa tagatgtaat ttttggtaac atttaaaaat ctcattaaga 119940aggataacat aacttttgtt aaaaaaagga agaaaaaatt tgaaagtaga agcaacttca 120000ggaagaaaat tacagtgcat gtgattccaa cactgagata taatcactgt taatttttta 120060tgtcttttta tttttgagct ggagtttcac tcttgttgcc caggctggag tacgatggca 120120cgatcttggc tcactgcaac ctctgcctcc cgggttcaag caattttcct acctcagcct 120180cccgagtagc tgggattata ggtgtgcgcc accatgccca gctaattttt gtgtttttag 120240tagagatggg atttcaccat gttggccagg ctggtcttga actcctgacc taaggtaatc 120300cacctgcctt ggcctcctaa attgttggga ttacaggcat gaaccactgt gccctgccat 120360tttttgatgt cttaaccttc aatattttgt aagcatttat atactttatt tatttattta 120420tttatttatt tatttattta cttatttatt tttgagacta agtctcgctg tgtcacccag 120480gctggagaac agtggcatga tctcagctca ctacaacctc cacctcctgg gttcaagcga 120540ttcttctgcc tcagcctccc gagtagctgg gattacaggt ctcatgccac cgttcccggc 120600taatttttgt atttttagta gagatgaggt tttgccctgt tggccaggct ggtcttgaac 120660tcttgacctc aggtgatcca cccgccttgg cttcccaaag tgctgggatt acagccgtga 120720gccaccatgc ccagccagta tacttttaga tagttatttt ttcctaacaa aatgggatca 120780tattgtacat aattttgtta catgtttttt cactgaataa atgctttgct tttttatatc 120840aataagtagt tttctccaac accatttata aagtttaatt gaattccatt atattgatgt 120900accataattt ttttaaaaaa ttatattatt gaacatttat gttgttggca attttttttt 120960cactagtatg gacagtacat cctcgattac ttcctaagga taaatctggg atcaaagagt 121020atacacgtct attttttcat actgctaact ttgttttgcc tatttttttt ctgagcaata 121080atctacagta atgcctcatc aggcagttaa gcaggcatgc taaataccag ataacactgg 121140gctactcaga aaagagatta tcctgtaatt tgcaagcatt tcacaagtta gaagactttg 121200ttgaagccag ttactatcct tgtcaattag taaaaatatc caagagggcc tgagacttac 121260attgaaaagt aaaataaagt ttgatcattt gagtgatgtc ggatggcatt aagtcatgaa 121320actaagtgaa acttaaaggt ggctgagaat gcaacaggcc tccagagagc aatggaggtc 121380cttgggtagt gataaaaatg gcatttctgg ctgggtgcag tggctcacac ctataatccc 121440aacactatgg gaggccaaga caggaggatc gcttgaggcc aggtgttcaa gactagccta 121500ggcaacatag tgagaacctt cctctaaaaa aagggaaata aaataaaaat aaaagtttaa 121560aagagagttt aaaaggcagt tttaaaagag acttactcag caagttttct gccaaattta 121620cagtattaaa aagaaagaaa gtgtgttttt gtttctgttt gtttttttga gacagagtct 121680tactctgttg ctcaggctgg ggtgcagtgg tgcaatctca gctcactgca acccctgcct 121740cctgggttca agtgattctt gtgcctcagc ctcccacaca gcagggatta tgggcatgca 121800ccatcatgcc tggctaattt ttgtattttt agtagagtcg aggtttcgcc atgttggcca 121860ggctggtctc aaactcctag cctcaagtga tttgcccacc ttagcctccc aaagtgctga 121920gattacaggc atgagccacc gcaccctggc cttgattgtg gttttttaat caatgagctg 121980ccatacttct gctctccagc aaaggttttc tatgagaatt ttctgtaagc taagtaaagg 122040aatatcttaa tattggaaga aataaaattt agtcagagtt gttttctacc tttgtacaca 122100gcaacactta caagtaattt gaagagtagc taataaaaat ttctgcatgg atggcttagg 122160cattttaatt tttttaaggt tgcctgagta aatctgaaaa taataaatta ttacagtttt 122220gctcaaataa agaacacaaa tagaacaaaa aatacataac tggctagatt acatgaaagc 122280ctttttccaa aacagaggtt tagaggccag ggcaaatagg caggaaaaat aaataaaggg 122340catccaaatt ggaaaagaag aagttaaatt agctttctta gcagatgaca ttatcttaca 122400cctagaaaaa cctaaagact ccctcaaaaa acctgtagaa ctgataaatg aattcagtaa 122460agttgcagga tataaaatca acatataaaa atcagtagaa tttatatatg ctaacagtga 122520acaatctgaa aaagaaatca agaaagcaat cccatttata atagccacaa aaagtataaa 122580atacctagga atcaatctaa ccaaagacat gagagatcta tacaaggaaa agtataaaac 122640tatgatttaa aaaattgaag aaaacacaca aaggtggaaa gatattccat attcatggat 122700tggaagaatt aattttgtta aaatgactat actacacaaa gcaatttaca gattcaatgc 122760aatccctatt aaaatactga tgactttctt cacagaaata gaaaaaacaa tcctaaaatg 122820tatatggagc taaaaagacc ccaaatagcc aaagcaatct tgagcaaaaa gaacaaagtt 122880agaatcacca cactacctta cttcaaaatt tattataaaa ctataataac caaaacagca 122940tagtactgat ataaaaacag acatagtaga ccagtgggac agaatagaga acccagatac 123000ctaagtccac atgtttacaa ccaactcatc tttgacaaag gtgccaagaa ctgtaacggg 123060gaagacagtc ttttcaataa atggtgctgg gaaaattgga taattatatg cagaagaatg 123120aaactagatt cgcttctctt accatacaca gaaatcaaat gaaagtatat taatgacttg 123180aatcttagac ctgaaactat gaaattactt gaagaaaaca ttaaggaaat gcttcaggac 123240attggtctaa gcaaagatct cattctgtca ctcaggctgg agtgtagtgg catgaacctg 123300gctcattgtg gcattgacct cctgggctca agcaattctc ccaccttggc tttccatgta 123360gctagaacca caggtgcatg ccaccacatt ccactaattt ttaaattttt tgtagagatg 123420gagtctcacc atcttgccca ggctggtctc gaactcctga actcaaggga tcctcctgtc 123480tcagcctccc aaagtgctga gattactagc ataagccact gtccctggcc agcgaagatt 123540tcttatgtaa gacctgaaaa agcataggct atcaaagcaa aaataggcaa ttgggattat 123600gtcaagctgg aaagcttctc cacagcaaag aaaacaatcc acaaagggaa tagattaccc 123660aaagaatgga tgaaaatatt tgcaaactat caatctgaca agggattaat aaccagagtc 123720tataaggagc tcaaacaact gtataggaaa aatctagtaa tctggtttta aaatgggcat 123780gagacctgat tagaaaactc aacagaaaaa aaaatttgat taaaaatgga taaaagatct 123840gaatggacat ttctcaaaag aagacagaca aatggccagg aggtacatga aaaaatgcgc 123900aacatcacta attatcagag aaatgcaaaa caaaaccaca atgtaaaatc cacttgccct 123960agttaaaatg gcttgtatta aaaaaaaaaa aaaaaacagg caataacaga tgctgggagg 124020atgtggagaa agggaaccat catatattgt tggttgaaat ataaatagta cagccactat 124080ggagaacagt atggagggtc ctccaaaaat aaaagtagaa ctagaacttc cgtgtgatcc 124140agcaattcta ccaccgggta tatatccaaa agaaaaaaat tagtatatca aagagatatc 124200tgcactccca tgtttattgc aatagtattc acaatagcca agatatggaa ttaacctaaa 124260tgtctgtcaa cagataaatg gataaagaga atgtggcata aagatatata tatatatata 124320tatacacaca cacacacaca cacacacaat gtggtactat tcagccataa aaaagaatga 124380aatcctgtca tttgcagcaa catgtatgga actggaggcc attttgttaa gtgaaataag 124440cgagggaccg aaagacaaac atcacatgtt ctcatgcagg tgctaaaaaa gtagatccta 124500tgaagacaga gagtagatta gaggttacca gaggccgaga aggggagtgg gaagtagagg 124560ataaaggaaa aaaacaagaa tataaatgta tttattacca ttaaactgaa catttaaaaa 124620ttgtaaagat ggtaaattat atatgtgtat tttatcttaa ttaaaatttt aaaaatcagg 124680agtttagaaa tttttaagag aagtgtgccc atagtgataa gaaagaaaga cccttttgga 124740aaattttctt gaacaaatta tacagtattt tcttaaacaa attgtacatt ctgtagcagt 124800taatacacca aataagattt cagggttacc tcttggagat tgtatgaaat aaaaacattt 124860aggtgggcat gatggctcat tcctgtaatc ctaaaacttt gggaggctga tgcaggaaca 124920atacttgagg ctagtacttc aagacgagcc taggcaacat agtaagaccc agtctccaca 124980aaacaaccaa aaaaaatagc aagtgtggtg gcacacacct gtagttccag ctactcagga 125040ggctgaggca ggaggaacac ttgaggccag gaatgtgaga ctgcagtggg ctatgattgt 125100gccacagcac tccactccag ccttcactgt agaaagagac cctgtctcga aaggaaggag 125160ggagggaggg agggagggag ggagggaggg aatgaaggaa ggaaggaagg aaggaaggaa 125220ggaaggaaat gtaaactcat ttgatttggc tgtaaaggat taatagaaaa ggaaaacgta 125280gtcactaggc tgagaaaaat tgaactctat tgaattggta taaagatcta agtggaggtg 125340tttggcagac atgatcatga agctttcact gaggaaggaa actctaggag gcaaaagcag 125400aaatgcaact catcaaaatt gaaatggtga caaaatatgt gcattcaaac ctgaaagtga 125460ctgaaagaga agcccaaaca cacaattttg gggtaagatg ggaaaccatt accaaagttc 125520tcagaaagag catttttaaa agtaagatta tagaagccaa aaggatatgt agtagtctgt 125580tctcacactg ctgtaacgaa ctacctgaga ctgggtagtt tgtaaagaaa agaggtttta 125640ttgacgctca gttctgcagg ccatacagga gacatggctg gggaggcctc aggaaactta 125700cagtcatggc ggaaggcaaa ggggaagcca gtacatatta catggtggga acaggaggag 125760gagagggagg gtgggaggtg ccactcactt tttaaaacaa acagatctcc ttagaactca 125820ctcactatca tgagaacagc aagggggagg tttgctccca tgatgcaatt acctgacacc 125880aggcccttcc tccaacatgg gggattacaa ttccacatga gatttgggtg gggacacaaa 125940ttcaaaccat atcagaatgt tagtgactaa agtaaatgtt cttgtttaac tctttaatgt 126000gtatattgag tgcaagccat atgcaggggc tattctaggt actggtggtt tactcaagaa 126060aaagggggca aaaaaatgaa gaaggtggcc aggcatggtg gcttacgcct gtaatcccaa 126120cactttggga gactgagacg tgagaattgc ttgagcccag gagtttgaga tcagcctggt 126180aacatggcaa atccctgtct ctacaaaaaa atgcaaacaa acaaacaaac aaacaaacaa 126240attaatcggg catggtgtca catgtctgta gtcccagcta caggttgagg tgggaagatg 126300ccttaagcct agggaggttg aggctgcagt cagccatgat agcaccactg cactccagcc 126360tgggcaacag agtgagaccc catctgaaaa aaaaagaagt caaaacaaat gaaaaaaaaa 126420aaaaagtcaa aacaaatatt cagtgtaaat gtgagaccat gtaaaaaagt ttaaaagtaa 126480aatatatagt ttaagcagag gatgggagac ggggaaaaaa ccttttctcc ctaactttat 126540atactccctc tataaattag tgcttatggc caataagaaa tgaataattt cttttttcac 126600cgttggtagt aaagtataat ggtagttaac acaaaaaact aaatgatata ttcagaacct 126660catactaaac aaagaaacaa aggcatgcaa tcacaggaca ggtggaaaca gtggttctga 126720actaaccaca aaccagaact accaaatgtg ctacaaattg tttagtaaca aaggaccatc 126780ccttcagaat tgaagagcac gtctcagtta tctcatgcct atgtgcatgg aacttaaagt 126840ctcaaaatta ctcttacaag atggcaaatt gaggctgtca gctaagctcc tagattgtct 126900gtttctccaa gaaaaataaa tttcagtaat tattaaggaa aaagcataga attgcatcat 126960gttttacatt tcattacttt tggcatgaca tgggagcatg gatgttttct acaaagtgct 127020ctgataaatt gaagaagagg ccaacaacag ccaccgaaaa aaccttcaag attcttgcca 127080gtatggctca ggggaaaaat tccctcataa ccacagattt gacttttcaa cttctgtact 127140tctgcatatg agtaataatc tctgaggtta agtattcatc ccatttagct aattgtccac 127200ataactccct gggtcttaga ttgctctata aatacctcct aagagaagaa tttttcaaat 127260gacagtttcg tttttccttt ttcttctttt aaagcaacaa agaaaagcac gtctgtgttt 127320atatttaacc aaacttaaac ttggagagca ttggccgtgt tgtcgacgtg tttcttttct 127380ctactgttaa attccttact gttccagtta ctcaccatca tactcacctt tgcctctgcc 127440acttggggtc ctctgttctg cagttgtgtt ctgctctctg atgcctccag gttttgctgc 127500accttctaga aattgctcac ctggataagg ccttggctgt cctttatgac tcatctcgtt 127560cagaagcctt ttgaatctct cttgaagaat attccctttg ctcagtccaa atacacattc 127620actcacttga atgctgcttc ttcctccagt ttcacagtgc tggggatgat cccgtaaggc 127680ctttaaatta cattataatt agtcatgcac ttctctctgc tctggggctg tttgaatcgt 127740tcactctctt tatacctcca gtgttcagca cagagcctag ggtataatgc gtatgcagta 127800atgtttcttg aaggagtgaa tgggcaagtg aaacaccaaa caaatactaa agagcaaaac 127860atgtattgct cttgtatatt aacacattcc gagaagagat gggaggaagg tcttgaataa 127920tatcaaatta tttcttaaga gatcttgatt tagatttttt tcaaaatgag atacatgttg 127980acactgctgt caacaaataa tcacataaaa gctagagcct ggcttttaag tatcaggggg 128040agcatgtgtg aataatcagc attgctgctg ttgaagctcc ataaagtggg aagcagcgac 128100tgcaaagatc cagagatgga catctgaagc ataggaaagg ggcagcttga atgagatagg 128160agcaggatct gtattgattg caggtcacca gatagaatta aaaaaatcta tgttctcact 128220agtggctaca gttttcaagg acaaatgact attagtggtt attgtatttt tcttgttttc 128280aatggagcag ctccatgact tagttacata agaagttaaa ggctccaccc ccttccctac 128340caatgtctta agctgtcctc cgtgtgcata caaactttgt ttccagactg ccctcgtgtg 128400actcagtccc tggaccagct tcccagcccc ttctgtttcc agcacatcct cctccacgtg 128460ttacaggatt acaaagcttt gcacagcctt tcaatagggt ttagagcaag aatgacagat 128520tgctacctgg taggcagcac tgactatagt tttattggcg ttgcgtagag tgactgcatg 128580acatgcaggt tgtgcttttg ttttgccagg aatttaaagg catttagcaa agccgtatga 128640aattatctgc cttatgtacc tcgaatgtga ggtaatgaac ttgtcattag tcgtgtttta 128700gtttagtgtt ctcgctggaa tttgcaaaag attaaaattc tgcacatttc attaagtctt 128760ccacatgggc tcaaaatacc atcccgcagg ctcgacctga cttgccacgt tgctttgaca 128820ccatctctga ttccagtgaa caaaactaag taagtgtgac ttacagccgc cctaccaaac 128880attgaaggtg tgagcctgca ctgttgtttt gtaatgacaa tgacaagagt ataatgacaa 128940gagtataatg acatcctagt ccatgaagac atgttttctc ttttccctcc ctctatgtat 129000acttacttac tcttaaggaa ataatataat ttctatttct gcttaaatct gccatctcta 129060cttagaatta ttttcccttg aaaaattaaa ttgcattatc catcagccaa atggaaaatc 129120tgattactaa atgcctactt ctagacatta tgaattacct gtaatatcac atttcttggg 129180cacttctcag aatgctatga ttttacataa aagcataaat tacagaatga gaagagtaaa 129240gcttagtgca tattatgcag gttcgcagag tgatatgtgg cctacgactg tcattgtaat 129300caaaattgat ttttgatcat ttataaaact aaaacaacta attgaaagca aatttacttt 129360aactgatgaa attcaagatg aagtgacagt agtcatgaat cacagttctg tagatctgct 129420aaaatgccaa tgaactgtta ttaatggtga aagtgtttaa tatattaatg ggaatccaag 129480taaggaaaat aaaacacata ttttgccctt accttaagtc atgttgacat catacataaa 129540tcaggtagaa tttgaagatg tttcatccag cattcatcat gaagcaacag agtcaatagc 129600gggcagttac agtctgtagg caatgctttc tggtgtggat tatgcaagaa acttacagtc 129660atttggcttc ctttattccc ctttgcatgt aaactaccag gtggtaggta gacccattct 129720tggctgccag tatttttacc acttggatag attctgctct ctgaggtctt taagacaaac 129780acagcacatg tacattgtga tataggagaa agaacatcag acagaggcag agaactgggc 129840ttgtcaaaat taagggtgac ctagagcctt agtgtcctta tatgtaagat gagaagcttg 129900gattaaaatt cattgctcct tacacttgat ttttatgcag cagaactttc ttcaaaagag 129960atcactcctg gaatcccaat atacaaaatg gataaaagta ggattgttct gaagtaaaga 130020agtaaaatcc agagccccac ttatttgagt catctcctac cttttagatg gttattaaca 130080ttgtttctag

ttcagaaatt ctgatgtttt atattaattt aaactaaagt taaattagga 130140ctagaagagc catttcgtgt gaaaatagac atagtctgag tgatttaggc aaacccatag 130200tgacagattt agtggcctga tacactggct tggaaagatc tgttccaagt cagtctcaat 130260acacaaggct cggtgaacac atggcgagca gtcttggtgg tggtcaagaa catggaattt 130320gctgtgagag agagcttggt tagggtctgg gctcttccat ctgttaactg caaacttgag 130380caagttattc aatctcccta atattcagtt ttctcattca taaaatggat tgataatggt 130440accttctatg tacagttact gtgggtatta aatgaggtaa taagcctgta aaactcctgg 130500catgatgaca ttggcctaca ttaattgctc acagagtgag aacttattat aaacacaggc 130560atttttgttg aatgactgac tgattgaatg aatgaatata gaactagctt tctatttgtg 130620atgtatggaa tatctctatt tcatttaatt tcattttgaa tattaaaatt caggcttgct 130680tttaaaccaa agtatttgct gatgcaaaga atgaaattct gactatgata cagttacata 130740acttttgaag aaataagaaa aatgctaaca cagcatgaac aactttgatt tagagaacag 130800agtctctgtt aaaatccatg ggacttgtca acttcatatt tttgtttatg agcataaaac 130860actctttagt gcatgtcgga atcatttgat gcttgctgaa tcacaggttg ctggaaccca 130920tccccagatt ctgattcagt ctgagatgag gtctgggaat ttgcattttt aacttgttgt 130980ctggtgatgc tgatgctagt ggtctgagaa tacactttga ggatcacttt ttcacagtaa 131040aagtcacagt cattaagcaa gttaactcaa tgagaaatga taatgaaaag gcatgtacct 131100aaatagataa aggacctata ccagctatga atttgagttc agcaataatt gtaaaatttg 131160taattctttt caggtatttg gtttttaaaa aactccctat gtatgctttt atcttatgtt 131220ttatatggtg tccctctttt cctctctttc tctctaatcc agtttttaat gtgaacatgt 131280ttaatgtgaa aatgttgttc aaagcagaag cgaacctttt gtgtaacctt ggcggtatta 131340agtttgtttg taagctattt ctgccctgtt agcttctgta ctgaaacacg ttttcttgct 131400tttgttgcag tatggaagag aagagagcga ctggacaatt gtgctatcct gaatggaaaa 131460tagaggatac aatggaaaat agaggatacc aactgtatgc tactgggaca gactgttgca 131520tttgaattgt gatagatttc tttggctacc tgtgcataat gtagtttgta gtatcaatgt 131580gttacaagag tgattgtttc ttcatgccag agaaaatgaa ttgcaatcat caaatggtgt 131640ttcataactt ggtagtagta acttacctta ccttacctag aaaaacatta atgtaagcca 131700tataacatgg gattttcctc aatgatttta gtgcctcctt ttgtacttca ctcagatact 131760aaatagtagt ttattcttta atataagtta cattctgctc ctcaaacaaa tgcaattttt 131820tgtgtgtgtt tgaaagctaa tttgagaaaa tttcataggt tacatttcct gcagcctatc 131880tttatccaca gaaagtgttt tctttttttt aaatcaagac ttttaaaact ggatttcctc 131940ccatcactgt tttttgaagg tcctccaagt ccgtgttaag gtaaatatct gttttcttcc 132000tgatgtcaca gcctgagcat actctgtgca ttaggaagac ctgagtgcat ttcccaccat 132060tgtcctttcc acattatgtt gtagctggct ggctgtcagg cgactacaag actgagggtc 132120ttgtgcctta tagatctttg tatcccccat ggctgacata tagtaggtac tcagtaaatg 132180gttttataat gaatcagtga acattttgct tctatagaag tgtaccttct ttgtttctat 132240attatgaaac ctctttatta gaatttgtga ttgattctga cagtgtatag atttacctta 132300tattgtcttt attttccatg agctactaag tcattagaga tactctgaag catagttagt 132360ttaggaaatc acttcatatt gattgtatta gaattatctt ggaattgaag atatatccct 132420agagcagggg accccaaccc ccaggccatg ggccacacag caggaagagg tgagtggtgg 132480gccattgagg agcttcatct gtatttatgg ctacttccca tcactcgaat taccacctga 132540actccacctc ttgtcagctc agtggcagca ttagattctc ataggagcac aaatcctatt 132600gtgaactctg catgcaaggg atctaggcta tgcgctcctt atgagaatct aatgcttgat 132660gacctgaggt gtaacagttt catcctgaaa ccacccttca ccctgcagtc tgtggaaaaa 132720ttgtcttcca caaaactggt ccctggtgcc aaaaatgttg gggaccactg ctctagagag 132780aggtcatgat atcataccaa ccaaatggaa atgacaaatg ttttatgtca agtgttaatt 132840gcagaaataa atcttttttt tttttttttg gtagaaaaca aagaggcata ctctgatttt 132900tatactctgt ttttgcaggt gctcttttct ttgaatggag atttgatgag caagtggtta 132960ggatgcaggg agagctacta tgggtgatat tttccttgtt taggagctgt gagttaaaat 133020tgtatccttt gtggtttatc taaggaaagt caaatcttga cagaaaacat ttttccttgg 133080aaggtcaact ctcagacatt gtattttggt ttccctcagt cctcataact tccttcttgc 133140tgaacatatt ttattctctt ttcagagaag gaaaataaaa aggattctaa aagtttgatg 133200cattggaaaa atttccttga ggcatttagc aacacataga aaatgggctt tgattctttt 133260ccaaaacttt tagccatagg gtcttttata gacagggata gtaaaatgaa aattgagaaa 133320tataagatga aaaggaatga taaaaatatc ttttaggggg cttttaattg gtgatctgaa 133380atcttgggag aagctgttct tttcaggcct gaggtgctct tgactgtcgc ctgcgcactg 133440tgtaccccga gcaacattct aagggtgtgc tttcgccttg gctaactcct ttgacctcat 133500tcttcatata gtagtctagg aaaaagttgc aggtaattta aactgtctag tggtacatag 133560taactaaatt tctattccta tgagaaatga gaattattta tttgccatca acacatttta 133620tactttgcat ctccaaattt attgtggcga gacttgtcca ttgtgaaagt tagagaacat 133680tatgtttgta tcatttcttt cataaaacct caagagcatt tttaagccct tttcatcaga 133740cccagtgaaa actaaggata gatgtttaaa aactggaggt ctcctgataa ggagaacaca 133800atccaccatt gtcatttaag taataagaca ggaaattgac cttgacgctt tcttgttaaa 133860tagatttaac aggaacatct gcacatcttt tttccttgtg cactatttgt ttaattgcag 133920tggattaata cagcaagagt gccacattat aactaggcaa ttatccattc ttcaagactt 133980agttattgtc acactaattg atcgtttaag gcataagatg gtctagcatt aggaacatgt 134040gaagctaatc tgctcaaaaa gatcaacaaa ttaatattgt tgctgatatt tgcataattg 134100gctgcaatta tttaatgttt aattgggttg atcaaatgag attcagcaat tcacaagtgc 134160attaatataa acagaactgg tggcacttaa aatgataatg attaacttat attgcatgtt 134220ctcttccttt cacttttttc agtttctaca tttcagaccg agcttgtcag cttttttgaa 134280aacacatcag tagaaaccaa gattttaaaa tgaagtgtca agacaaaggc aaaacctgag 134340cagttcctaa aaagatttgc tgttagaaat tttctttgtg gcagtcattt attaaggatt 134400caactcgtga tacaccaaaa gaagagttga cttcagagat gtgttccatg ctctctagca 134460caggaatgaa taaatttata acacctgctt tagcctttgt tttcaaaagc acaaaggaaa 134520agtgaaaggg aaagagaaac aagtgactga gaagtcttgt taaggaatca ggttttttct 134580acctggtaaa cattctctat tcttttctca aaagattgct gtaagaaaaa atgtaagaca 134640aaaaaaaaaa aaaaaaacaa acagaggcag aggcaggcag tagcaagaaa gcagagcgta 134700acatcagcta gatggtaaca tgcaatgtca gctctcttga agacatggga aacctaagtt 134760acaccttggg ttaaaattct tcaccatatt agttttgttg cttcataaaa tttacctaag 134820caagtggtct tgcttgcctc aaatccaagc agtcttgaac acttggaggc aattaatgag 134880tatatcttag tcaaaagaat tgttggagct ttttattaaa gctacagttt cagttctgct 134940tttggggaat tgtgctatga aagcagctgc caaaataagc tcatttattt tcttcaatcc 135000cactcagtgc tcagtcacta tattctgttt cctttttttt tttcaagttg catatttggt 135060ttccccttat gattgggaaa gatgaatttt cagcagaaaa cattgtttgt tcactttcaa 135120agagtgatag tttctaaaac atttagagca ataaatattc atcagaggta ccaagtaagc 135180cggcagaaga gttaagggtt agagaaatcc cttatttcat gtcttgactc taaaattatc 135240aaagtacttt tccttgtaat gtggatttct tcttatgcgg atatgcaaaa acttcagtta 135300tacgtagtaa tgctagcagg taattttagt agacatttta taacaactgt cactttgttt 135360cgccacatgt agagtttgtt cagctatttt ccagatatct ccccacaaaa ggaggcaaag 135420ggtaccagct tttcaatgag cattacctat tacttggcaa agatgatgaa gactctatta 135480atagttcatt tgataaatgt tgacataacc aacaatagag attaggaagt tagttttaag 135540aaatcaatgg catatagaca ttaccctcat ggagtttgta ttctactact tgaactgatt 135600gtagctataa aagcatagtt agatagctga atagttagat cataagcaaa gaaggccaga 135660acacatctct tatcaagaaa tcaatgaata gtttatctca tttttaaagc aactttatcc 135720ttctttaatt ccttcctttc ttctagtgca aaactactta ataaggttgg tgtttaggtt 135780agtgttcaca ccattcctca tctggtgtga attaccttct ctttctttac tatttactac 135840caacctagta catgtgttga ctgaattctt ttcaaacaat gttgagttat catggtgcac 135900ctaataaatt aacaccacag attacagcat ccttgctgat tttctcagca aagccagatt 135960agatggaaat aaacaaagaa aatgatccta gagtgaattt ttctagaaaa tatctattat 136020gaaccatgct gtttaaagta ttagcttgaa ggtgatggat ccagctattc agaaaataac 136080tttcatataa ccatgatttt gcacagtatg aggtcttaaa tgtgtggaaa gagataaatt 136140ttttatcatt accacaaacc ccttttaaag attcaaaggt ggaagaaagt gatttatttt 136200ttctcttcag catacatata taaaagactt gtcagatgtt taatttgggg aggttgataa 136260tgaaacatat caacagagta tagtagttat agtagtgttt gtgggtaaat aatttcctgg 136320ggtcagacat atataaacat atttgcttca aaatgataaa ggcatgaaat cagtcttaaa 136380aattgaaatg ggggtgatgg gggagaaaaa gaagaacaaa tttgaagtgc cctttcaaat 136440ctgctggata caagtattga agttttaagt catcttattc tgtctgaaag tgtatttttc 136500attctacaat agacccaatc aacaagacgt ataacttgag ttgcatgatg ttcagtttat 136560gtaatctact gttgggatgg taagaattga tgtaggctgt ggtgtaagaa tgaattaaaa 136620tatagtttca ctggcttttc tctacatatc cactatcaca atggctaggt ttcctgttgc 136680tcactattgg attctggaga aaaatttaat gaaagatgat atcagaggaa gaataagtgg 136740aggtagagaa gaaaggaatg atagaggagg ggaaaaaaac aaaacatatt tttgtgttat 136800ccaaaggagc tttttcctta ttctgtcaag cattgagatc ttcttcagct ttcaatgtag 136860ttgctaaata caaataatgc tactaggtag tgactaaata tagcaaacac ttcatcagat 136920attagaatta ggtcacacta ttgaggttat aatctgaagg ttgtgttaca tagaaaccac 136980tttagattat tatcaacttg gactaggctt tattttataa tagcatagta agtaatatct 137040attgtgtcat ttcttcaacc attttattct aagatccatg aagcttcttg aggccaaata 137100aaataataag tttagacaag aagtagattg tgactttttt cccttagaga tactatttac 137160tatctcctat cctgataggt ggaaggttta ctgaattgga aattggttga ctattagttt 137220ttaactaaaa tgtgcaataa cacattgcag tttcctcaaa ctagtttcct atgatcatta 137280aactcattct cagggttaag aaaggaatgt aaatttctgc ctcaatttgt acttcatcaa 137340taagtttttg aagagtgcag atttttagtc aggtcttaaa aataaactca caaatctgga 137400tgcatttcta aattctgcaa atgtttcctg gggtgactta acaaggaata atcccacaat 137460atacctagct acctaataca tggagctggg gctcaaccca ctgtttttaa ggatttgcgc 137520ttacttgtgg ctgaggaaaa ataagtagtt cgaggaagta gtttttaaat gtgagcttat 137580agatagaaac agaatatcaa cttaattatg aaattgttag aacctgttct cttgtatctg 137640aatctgattg caattactat tgtactgata gactccagcc attgcaagtc tcagatatct 137700tagctgtgta gtgattcttg aaattctttt taagaaaaat tgagtagaaa gaaataaacc 137760ctttgtaaat gaggcttggc ttttgtgaaa gatcatccgc aggctatgtt aaaaggattt 137820tagctcacta aaagtgtaat aatggaaatg tggaaaatat cgtaggtaaa ggaaactacc 137880tcatgctctg aaggttttgt agaagcacaa ttaaacatct aaaatggctt tgttacacca 137940gagccatctg gtgtgaagaa ctctatattt gtatgttgag agggcatgga ataattgtat 138000tttgctggca atagacacat tctttattat ttgcagattc ctcatcaaat ctgtaattat 138060gcacagtttc tgttatcaat aaaacaaaag aatcctgttt gtgtggtttc atgaaatcag 138120cattgttgaa tgcatgaagt aataatgcta aattaacatt tttatgatgt ctcaaggttt 138180ctggtcaagg gaagtaaatg taggatagta tttttacacc aaaatgacac agagagaatt 138240gagcacacca gaaagaccag aaaccacacc actggataga gattcaatat gtttcttttt 138300caaacatttg gacaagaaaa aaatgggcat ttaaaaattc ttccttcccc tggttatgga 138360tttatctgta gtaaaactta gctttgtcgt ttgagatttg cacagaatgg ggggagtaga 138420ttacctcttc ccattcattg tcataatgga tctacatcac tgataaacac catacttcta 138480tatgtggtta actagcttta gaataaaaga cactttaaaa agtaaaaggc ctagagatct 138540tcaatgaagt gtccctttta gccaaaccag gccttgcaga aattgtcctc aaaagcacca 138600agggagaaca aagccaagtg cagaattacc caagggtcac acattttgta ttcattttct 138660tataatttgc ccaaatgatt tgaagtacag caaaacctga agttttgcaa agagttactg 138720taaactgaac ttaaaaatgt cagagtgctc ggtgacccac ttctccagac cctgtcaacc 138780tgtgaaaata ttggccttta ttcagatctc tcaagaagtt acgcgcagag tttggaaggt 138840ctaggcaaag gttattagtc aagtgttctt acagtgtcaa cgctcaattc ccacaagcgt 138900gagaaagaga gacctgtcat tcctgagggt gatgacatac atttactgga gcttatataa 138960tttatcagat aagacagcag tttccttcag ggtagaaagt gtgttttcta cattgattta 139020gtacaaaaca aaaagaaaag gggatatttc aaattttata attatttttc tgctaagctg 139080attcagtgtg atttaagcat atttttcaaa tcatgaatct gattccatat acatatgtgc 139140cttatattgt gataatttat ttttaagtga aatatgctat catagcctga ctttatgtat 139200agtggtgaca acttgcagga tcgcatttct gtaaccaaac ggccgacagc tgaggtgtag 139260atgcttccta tggtctgtag aataatcact gggcttgttc tctagctatg tctgtatgca 139320atcgcgacag tgttgatcaa aacccatgat cattctctcc aaaggtcttt gtcactaagc 139380cactagggat tctgaaaagt tcgtgagctg aaacaaataa attgagttgg aagatt 13943693130421DNAHomo sapiensmodified_base(28255)..(68254)a, c, t, g, unknown or other 93cctgtctctg gtgtgccctg gcccccgact tggaggcctc ctgggccagg ccaagacctt 60ccccggcagc gatggtctcc agccacactc aactgccctg aagggacatt tcctgcttat 120tcccttgccc ggctgtgtcc tccacccgga aggcctgtgc cttcttcgcc tgcatgtcct 180accctgagga ggctcccttg gtctttcatc gctctcccta tgggtcttca cgccttcccg 240aaccaccgcg cccaagcagg agcacgttct cggccctctt cacagggcgc tcctcctcac 300aggggtgccc gggattttta ttctgtgcct tcctggtggc tcctacaagt ctggaagggc 360aggaggcgca tctcactcct ctgggtcccc tcccctagcg cctggcggga gcccaggctg 420catttgtgga attcatgact ttttctctcc tgctcaagct gaacacattg ctggctcctg 480ctcgggtgga gcccggctaa ttagagtgag gggctccccg tagggcgaag gggtgcgctg 540tcagatgtgg cattcccgtt ttacggagac acacggtgtc ttacacgcca gggagaggtc 600tgagacgcaa agagccgtcg agcgggctgc gggattgctt cgctgtcacc tccgcctgca 660gccacccttc cgcacgcact tgtgtgtgca cccaggccaa catggaaggc gccatcctaa 720cttctgccgt gagcaggtgg gagggaagag agacgagagg tattccattg gttgtctggg 780aaaatgaatt gcaccttccc ctcccttgcg gaggatcaac ttttcccacc ccctcgggtg 840ggcactcgca tcctggggcc ggagcctgaa cccgggagcc aaggggcccc agttccaggg 900acgtgaagct gagcgtacag cgggcgctcc cagacactgg ggaaagtgct ttacgatgtc 960ccgagtccct ccagtctcgc cagcggggcg agcgtgaggg tgccccgacc gaccagcggc 1020cccgggtgca gggtggcggg cccggcggcg cgcgtccccc tccccctcct ggcggcccgc 1080acgtgtcgcc cgcgccgcgc ccccacgggt tacgcgcggg tcccgcagcg ccgcggccga 1140gccgggctgc ccggcccgcg gacacagcgc cggccgccgc atcccgtgcg gggccgcggc 1200gcgatgctgc gctggaatga ggaagcgcgg cggcgagggg agggcccggg cgcggtgcgc 1260gcgggggtgg cggcggcgcg ccgagcgggc ccggcgcggg cgagcgggct gcagccggcg 1320gcggcgccag caggtacggc ccgcacccgc cgccgccccg gcggcctttg ggggctgagc 1380cggagcccgg cgcgattgca aagttttcgt gcgcggcccc tctggcccgg agttgcggct 1440gagacgcgcg ccgcgcgagc cgggggactc ggcgacgggg cggggacggg acgacgcacc 1500ctctccgtgt cccgctctgc gcccttctgc gcgccccgct ccctgtaccg gagcagcgat 1560ccgggaggcg gccgagaggt gcgcgcgggg ccgagccggc tgcggggcag gtcgagcagg 1620gaccgccagc gtgcgtcacc ccaaagtttg cggggtggca gggcgcgcgc tctggccacc 1680cgccgctctg ggcggcagct ggtggcaacg caagggcgcg gcgggggcgg ccggcgcgga 1740gggggccagg tacggggccc gcgggcggcg ctgtgcgcgc ggggcagccg gtcggccggg 1800agcgcgaaag cctggtctga gccggctggg ggcggggagt gtggcggaga aatggggaac 1860aatgcgagtg agcaacttca ggaagtcatt gtgaaagaaa gctgggaaga gctccgcggc 1920caagttagca ggacactcta acaagtgact gcgcggcccg cgcccggggc ggtgactgcg 1980gcaagccccc tgggtccccg cgcggcgcat cccagcctgg gcgggacgct cggccgcggc 2040gaggcgggca agcctggcag ggcagaggga gccccggctc cgaggttgct cttcgcaccc 2100gaggatcagt cttggcccca aagcgcgacg cacaaatcca cgtgagtgtt ttcaaattga 2160atttcaatag gaaaacttgg ggtaactggt gaatttaaaa aaaaaaaaac acagtaaaga 2220aaagcggtaa ggttggtaga ccctggtgtc gctcaggtcc gcctctcttt tctgaggaca 2280gtgagagagt tcacttctgt caagcgtctg ttgctctgca ctgtgccagc aggtgcagga 2340ccaggccgac atgggacact tctgagcagc cccgctgtca ccaggagagg agttctagct 2400cccaaccata tttaaattta tgtagaccta catataccca cggaagtcag cctttataaa 2460gtcgtgtgta aagagttttc cttatatttg agccgggagc tttcttttta tactataaat 2520atgatgagat cgagtctgaa cttaatttct gcaagagagg aattatcccg gctttgaaaa 2580gttagtcctt ttgctgaccg caggtttgac gctcaagtca ccaaaccttc tcaggaaaac 2640ccttagtaat attaaggcat caggttactt gcggttatat ttgaaatgta ttttaaatat 2700ttgtcaagca tcgctgctga tgcctaagga acctcgtgag ggcttgtttt tccttctaat 2760ttggaggcat ctaatgaccg aaaaccgtag cgattccata gggtctgacc aggcacagct 2820ttcaaatgca gcttccctct ctctagggac tgcagcccac ccagactgaa tttcaatgcg 2880gtgcgctttg cttaggttac ccactcacaa tttcccactg cgccgcaggc agtatatttc 2940agctttgaga taccttgttt taaaattcca gacaaaatgg tgttgaggaa atgtctcctt 3000actagtccca tcaacttctg ttaaaagagg aaaatttatg gaatttgaaa atactgcgta 3060tgatatttaa actttcatag acattcaaat gcttttaagg ccaggttcaa tttggttatg 3120agtcgagggg tgggggggac ccacatagaa atgtcctggg tcctcttgag tttatttctt 3180tgtttgaaga tgtttgttca atgagtttta ttgtactcat cttttatatg gaattttaaa 3240aagtaacaat ttcagtatta tttatattag aatgtgtcag aattatttcc gtgacaaatc 3300agatcatttg ggctatggct taaaatgtac acgaggcaaa tattcatgac aagaagattc 3360accttcttac gctggcatct tgtaaaatgc agaacaagtt aaagaaataa tgtgtacaca 3420tacaaataat gatgtcacat taaaaatact acactattct tgcttgatgg aatgtatctg 3480atttccaatt tcaccatgaa catatttcat acatttttta catgaaaaaa aacgtgactc 3540ttaagtctca cagtcaatca gagctggtga ccagaacatt ttattgaact aaatggtcat 3600gttttcttcc ccttttgttt cacggtgaga gttgaaggaa ggagtttaga aactctccag 3660tacttgttta attcatcagt gttctaatta gagtggtacc tcttggaaaa ctacacaccc 3720ccctaatgca gaaacatcat agcaataatc acccaccctc agggtctcca ggagaccaca 3780agggctgcag ataaaagtct ggatgtgtta ggtttgaccc tttcgaagag ttttacacag 3840gctcctaaag agaagatcag ctgtggccgt ttgtagccat ttcctttgtc gaaaaactaa 3900gatcgcagtg aatgtattag ccaagaggtc taaagccctg ttgtactgca ggccactgtc 3960ttccttgttt gactagagac ttggagtttg agaacagtgg ttctttggtt tggatacatt 4020ttttgttctt gatttggatg tgtgtgtttc atgcgtggtt aatatagcat attttcaata 4080taaatgtcaa aaattttgaa ataggaaaga actctctata tattaatgta cttatacaca 4140cacttcaaga ttatgcattt attaacagat acatgaaata aattccatgt gcatatgcac 4200atatgcacac agagcgtgca cacacacagc atgcacacag cgtggagtga gaggcatggg 4260gcagtgtgga agagttttaa catcaaacag acctgaaatg agtattaaag gcccccttta 4320tttttaaact tttactaaaa caagatggat ttccctatgt tatataatgg tgaattttag 4380gcataaataa cgttttttga gtgttgcata attgtacgta ttaatgtaat gtaactgtgg 4440ttaacgaaga attcatcaag gatatcactg ttttgtggca tttttttttt cctcctctaa 4500tctttggact tgtgaaataa tttcactatg aaataaatgt tggttcttgt catattctaa 4560gggagattga tgtaagtggc tccactccag cttacagaag gtaaaccacg acctttttgc 4620gttctctgaa aacgcttgtc ttccgatgcc tctgtttcta agactgacaa gcactctggg 4680ggcactgtga cgcctgcttc tagcggcaga gttgctgcag ctcctgtcct ggctgtgaac 4740attgttctct ctctggtgtc tctatgttca taactacaga gacttcagct ctattccatt 4800tcatatttgt gctgaataat cattccattt tatgggagaa aacacaagat gtaaaagcaa 4860caagtgaccc atcctttgaa gcttacaaga agagaaacat taatctattt cacgtcttga 4920aaacagatca gttttatttt gctcaaaaag ggcacatgta catttttgat ctaggtctta 4980gaaacgtaga gtttcagagg atcagcatta tacacactgt cacacacaca cacacttaaa 5040attcagatga ggaacaagat aggaatgagg ttttgttagg gacgcagagc acctaaaacc 5100aaaggatatc gacagtaaca aagctgtttt tactgtagtg ctgactgaac actcatgctg 5160gtgtcttcat gtggaccatg gctttcttgt atttctttgc agtttaataa atgacttcat 5220atctcaggtt acctttccac atctcctgga atatatgttt atgtccttaa agtttcagtg 5280tcgtcacttt agtagcttta gtttgagttt ttaaatgttt ggtaatattc caacaaatat 5340tttttaagac attatgaaac cttatgaagt gccatatatt acaagtgaga taaaacagca 5400agcaaaagaa ggtttgcaga aggtttttaa gtggcgaagt gcgggcctgc ccattttggt 5460gtctccttgg tggttactcc tgagaagggc ctggaggaag agcaactgag gcctaatcta 5520caggcaactg ccaaattgtt tcagttgacg tttttccctc tcatgtttga ctataataaa 5580taggtagttg ccagtggagc cttcagccaa ccacctggta ataaactgtt

aaaaatggtg 5640caaaccctag gtcacaggtg tgggggccat ttgtcttgcc tgttaacagg cctggcctta 5700attcttttct cccatggcca tttctgcctt tggggaactc acaattcctg ttgactaaaa 5760gagcaccctt ttccaccaca agcctgacaa atcagacgtc cacataattt ctgaactcgt 5820tttggttagg acaggaagca caggctccct tcctgtctgt gttttcctaa gagaaaacgg 5880tcttccctcc ttttttgcat atttggcaag tggttccacc tttctctgca ccctggtgga 5940gtgtgaaggc agcagaggaa ccttttggag gaggaagagg acacagaggc cctgtagcca 6000ggcaccaaga tccctcccag gtggctgggt ctgaggggaa ctccgagcag ccctaggtcc 6060tcaaagtctg gatttgtgtg gaaaaggcag ctctcacttg gccttggcga ggcctcggtt 6120ggttggtgag tgccacacgg tttctttgtg tgcttgcatg gattggaata gccattgtgt 6180tcttccgtct tccctgctgg tgtttccaca gtgggtggcc tgagcccaga gcagctcccc 6240atatccctgt gcaggccacc tgtctcgggt gatggagagc atcattatgc tccgtctgaa 6300cgctctgctt tcggatggcc ccatgctcca cctcctgata gctcgtggcg cggggccacg 6360gcttaacaaa tggctgaaaa tgggtcctaa ttagtggaaa agtgctttct tcatattttc 6420tcactcgagt gtgcagtgat tcatttttct tctgcaatca gctcactgct aaagtaaatc 6480tgactctctt cccgccattg cacaccaaaa gttaactcta atgggtagga ggttaggttt 6540gttgagagag caatgcagta aaaagagggg atccaatgtg gtcttgtctg tctggtcttc 6600ctttcttcgt tttttcctcc cttgtcttct ctgtcattcc cttccctcca tttgccttgc 6660ctttcctgtc cttcccttcc cttccttccc ctctttcttt ctataattgg tggggggttt 6720gcacagactg ccaaaacact aagaactgtg taaagtgttt ttgaatggcc ttacacatat 6780tgaagtagat ttttatgctc catttttgag atcacacact aaaatctata cctttaaagc 6840attttctgtt agtttgaaac tatttgaaaa tgaacaatgt ggtttagatt agagtcctgt 6900tctgaagcta ggagttccac tatgaatatt gatttatcag tttttgacaa atttttgttg 6960ttataccaga ttttcactgg caaacctaga gcaaataaaa ttccacataa gatacttccc 7020tagacctaat gggaaaaatg tttaatttag agtctttagg agaaatgaga atgaggaatt 7080gaccttttgt aagcttactt ctgaggcact ctgaagtgtg ttccagtgct tttaatggaa 7140actagagaga gccagcaacc ccctagtgtg agccccactt ttaaccggaa aaagtgacct 7200tttcctcctc ctttgtgctg agttttgcgt agggcagaaa attaagctga tattcaaaga 7260gattcactgc aaaaacatat tgataaatcg tatattctat ttcattaaat taaaaccata 7320ctgctaatta tctcaggttg ttaaacataa ggcaattaat tatcatttta aaagttggta 7380ggaagttgtg agtacttttg cagtatgagt gttttcccgc tttagtatga ggttgtgtat 7440gtttgcttga atttacagaa ttttcacttt aagagcagac aatgttttgt taaagaaatg 7500aaatttgcta aaaaggagca tgtaaagtga aacattaaaa ataaataatt tcaacttact 7560taagagctgc agaaaaatct gattgctgtg tttaaaatga attttcccac atttcgctct 7620cttatggaca ggagcatttt ctgtcaggtt ataaataaag acatgcccat tttttgtacc 7680cccacaaatg aggaagttgt aagctctctg aggttttact gatgagcccc ctccccctgg 7740gtttgcatga agagatcata ggccacaaat aaaggactac aaaatggggt ctaaactatc 7800ctggtggggc ctgataccca cgtttcgcat ggaccttacg atgtgatgaa tggttttggc 7860atgagtgtct taagaatgct tccagattcg ggttacagga cagccagcgc tgagctccct 7920attgcagaac aaagtaggaa tctagaactt tcttgctaac aggatccagc taaaacacca 7980agttagattc ttaaatgatg ttcttttctg tcattatttg attgttgtca gtagcagtaa 8040ttgttaccaa gccattgatg cttctattct tccctttgcc cttctgagac acagctcatt 8100ttgacttcag tggaacccct cgaaggtggg gtgatgagca aggtgaattt tcaaagtaaa 8160gctactaaga gaccaaacta caatttaagg aacctgattt ttgaatcaaa ttccatatac 8220tgtgggtata gttcaacata gattaatttc ttatagttat tatgaaaaaa atctcatctt 8280gatgatagct gataattttg tgggtgtcgt aaacaaaaca gaggtcagaa ttcagtccct 8340tggggaaaat ttccaattag taggaaacca agtggcctac cttagtttga agacacccat 8400caggatgtct gcaccttttc atcctctctg gaggaaagac taaataccca ttattgtata 8460taggtcaggc caaagcagcc ttttatattg caaggaataa gaggtaaata gatatatgtg 8520caacaatgaa tcccctaatg tgtttactct agaacacatg ttctttctgt atttatatgt 8580agattttgta gatcttgtct taccacctgc taatggtaga tactgtatct aaataagttg 8640aggaaaattt atagtaccta ggaatgtgtc ctcagtgggc caatcaatca atcatgactt 8700caggttattt ttaataaata tacacgtatg ggttcataaa caatgggatg ttcttgtgaa 8760gatctaaata attttacttc tttgggacta aataaaatat agcttttgcc aaataaactc 8820acacaagcac ttattttaat agaagtcaaa tggctttgca gaaacttcag ttttacaggt 8880gcattgtttg aaatgttacg ggtatacaag tggatttctc tattatgtac agtgttaagt 8940ttgagtttca aaatgtccac ctgaaatgat ttacttgtac gttaagataa tttaactgct 9000aagaaggcaa gataaagcat tctttgtgac accatatggc cttgctgagg gaaaaactta 9060ctgttataag tttgtgttta tctctctttt taaaaaaaaa tgaagaaaaa aacgtttaaa 9120ataatgggaa cacagcagtt cctggggtcc tctgtctctt tatcttatta tagtaaatta 9180ccaaaaaaat aatgacctgg ggcatgtctg tgtggaccct tcttttagag gcagtttctg 9240tgttttgtaa agctgtaggt tctattttca ttgcacttca tattgctgca cagctcctga 9300ccatgcatga aggtcctctg aaatcggtaa gagggcagaa gaaaatgatt ctaaacttag 9360atttttttaa cttaagtgat gaagtgtgaa acgccattta tatttgagga agctacctag 9420gaagtggctc atgtcgatgg cccaaatcag aagagggcct gtaaaagctt ctatcaattt 9480tgactgtgta tgcttctacc atggcggctc aataaacagc agtattagtt taagagtgga 9540tggtacagta gtatagacgg gaagcctctc ctctccgtgt gaaccgtgca cccctatgag 9600agggtagaga caatacaata tgcctgtaac gtcaggacag acagtcatgg ccagcttgaa 9660ctccagccct gggcttcttg cagcaacaaa cgtgaacaca gaggactgtc tccaactcca 9720ctttctctat ttttaaaaca actttttgaa tacagtatct gccatctttt cttatacctc 9780actttgaaac aggtggctcc actgtggcat ttaaaatgtt ctgtttcttt tccctctgta 9840tcaaatacct ctttaccaag aaaacattca aacagcatag tttttaactg tattttgaaa 9900ggtttcctta gttccctttg acccttcctc ttttgcatat cagttcctgg ccataaaaat 9960aaaaaatgct aggacagaat tgcacatctg agctgatttg ccctcaaaaa gtttcacagt 10020ggaacaaacc gcaggaggag ttttctgtgg ctcagttaaa tgtcggggga gggtggtgtg 10080aaagccaaat tggattcctg ctttcctgtt taaatcttgt ttttcattgt tatttgcacc 10140agcaatactc tgtggaataa tcatgaaaat gtgtagattg gcagctaatt tttgaaaaat 10200gaaaagaatc agaaatgaaa taagagtgct cggaagtttt tatgttctct caacctgttt 10260tgtcaaattg ttacgaaaac ctataaggtc tctttgacta gatacaaaga ctttgcacat 10320tgccttagct ttctcttgaa gcatttcctt ttttaaaata cagtgtaatt cacagtgata 10380tgatagattt gcaaaagtaa aatctaccag tctgaagatg aaaggacttg tctcttagca 10440ggaataatgg gttttattaa agaggtctgt gacctaaggc attttaaata aattacaggc 10500ttggtccctg tctcccccat gtatctactc ccttcaatat aagcatcatt gagtatttaa 10560ggaaataacc ccaaatgtaa ctctagtgta gcttcacttg tcagggagga aaaagtaaat 10620agcatacatt tggccaaata accagaactt tactgtagaa gttttatgat gaaatttgcc 10680tttagtgcag agtattacaa agatcatgtt tagtttctag cagtatataa gtagcatcca 10740tccttatctg tcatgcattt ggagtgtgcg acccctgcac tgggctgcaa cattctgatg 10800ggcaagagtg ctagggagaa agaggcatca ccatcagact gcacgggttc aagtgtcagc 10860tctgtggttg attagctgtg tgacctgggg aaagctattt ctcttagcct tggttctctc 10920atctataaaa tggagataat gatgcagatg ccttgggttt aattgggaga gttaaagaca 10980catttacata tttagcaagt aggtgttgaa ttctagctct acattggaca ctatgccagg 11040tgctcaaata aacaagtgga caagacagac aacacccatg gtcttatgag gcttaaccat 11100ttgcctcttc aatgccagaa acttagtagg ttgattagat aaagccagtg agtaccagta 11160tccttttctt tgcagccttt tcctggcaca ctaaaaatac tcagtacata tgaaatatca 11220ctggacaaag aatccccctt agagtaccag tggagaagga aggcatttgc ttaaaagcaa 11280accaacagaa agacattgta aggcagttgt ttaagtctca gagacctata atttttttct 11340tttttctttt ttttcatctc gctctgtcgc ccaggctgga gtgcagtggc acaatctcag 11400ctcactgcaa gctccacctt ccgggttcat gccattcttc tgcctcagcc tcccaagtag 11460cagagactac aggcgcccgc caccacacct ggctaatttt ttgtattttt agtggagacg 11520gggtttcgcc gtgttagcca ggatggtctt gatctcctga cctcatgatc cgcctgcctc 11580ggcctcccaa agtgctggga ttactggcat gagccaccac gcccggcaac tacaattgtt 11640cttaaagctt gtagaattac tgtgtgctac caacagacag gctaattttg agtgaccctc 11700agtactttgt acagttaatt tggcacgctg tgtacttagt ggctttttaa cagctataaa 11760tttgggctgc tagaaaagta gtaaagttgt gattcttgac aggcatctat ctgcattttc 11820atttttactt catttgtcta gactcagctt gtcagaatta tggaagagac tccttgtgtc 11880agggcaagca ctgtgaagag aggtattcac tgtcagaaaa gagaggggag ctggaggcag 11940ctcagaggcc tgagacccgc ctccacagga gccccagcag gttcggtgga gctctggcca 12000cactctcctt tgggatgctg aagtcagaat gagttcactt cccagccagt cttgccaagg 12060ctcctcacct ggaagcagca actgcccagg gctgttggat gtttctcccc aggggacagc 12120caggtcccag tcccgcctcg gtgtggaagg aggaaaggca gggtccagga agctgtttca 12180ggacaggccc aaggtccccc agggatgcct ttcagggtca gcggaggctg taaatcagca 12240gggcccacac ggcctggaag aggcccctgt gctgtcggct tgcccggctt gcccggctcc 12300tagtccggct tctgctcctc ctttgtaaag ttatggatat gctaatagtt tccaactgag 12360actaggaaag taagtcctac ttgacactgt ttggtcagaa agagggagag aaaggagaag 12420gacagagaga gactgagaga gagacagtct cagacaaagg gagacggagg gagggaggga 12480gagacagaga aagagatggg aggtaggtgt gggaggaggg agagatgcag aaggcagagg 12540aaagacagac agagatttag acctcccaag tcagtgagca gtccagagtt ggagtggagg 12600gtgcctggtg gcttgtgact gcagactcca ctccccgctc ctagaggcac agccatggac 12660agcttctgtc acgttggccc tgcacttatc tctgcatcta tttccccttg tgcaagattc 12720agaactgcat gctccaaaaa aacaataaaa gcattcatgt tcataagaat tgcacaggta 12780aaaggtagtt tgctgatatt gttgtatttt ttactatcgc ttcttttagg tcttgcctga 12840aattgtttgg gtttcccagg caaagtagaa aactgcggta cgtttctgtg aaataattat 12900tccttctggc atctcccttt acagacctac tgatcttgat ttttcattta ggtgaaagtt 12960tgtgaaaaca tgccattagc ttgctttgtg attaactcct tttactgaat gtgagctcct 13020tttaaattga ggccatatca agcttaaatt ccatatttta cccggcactc tgcatttctt 13080ccatgtggga gaggaggggc tcagtaagtg ctttgtaaaa tacacagccg aagtgatgca 13140cgtgctaaca aaggagtgtg acaggactta agtgcccttc tagacacttc aggctcccct 13200ttgtaagctg tcttggaaga ggccacattt cctttccctc aaacagtttc tcattgtttg 13260attattcttt tagcctttct ctggaagcaa agccactttt acgagaaagt cactgctttt 13320tcatctcaag agatgcaagt ttggagtttg gggaagtttt caggtgcccg tcaagtcatc 13380ctttatgatg tcagacgagt caggccacag aattcacagg gctcagtgca gaccgaaaac 13440ttgaggcctc ttgttcagaa attattaaaa attttggtga acatcacccc aagcaaagag 13500atcccctaag caccagcccc caagcaactg cactcataag cccatgaagc cccctgctgt 13560cagaaacaat gtggttgaaa ttgtgtatgc acttggaagt gagatggatt gcaaaacaca 13620ggtctccatg ctggggcagg agtggtgata gggcatggag tggaaatgtc cagcaggccc 13680acgtgcgaaa atgcagagct ctctggctct tgcagacttg gctgctgaca atagacgcgc 13740tccaggaagg tgctcgctgt ggtgtgatct gctgcccacc cctagctccc tccaggagac 13800tggtgcgggg actgtttgca aatgactgca aaagtaagaa ggttcccaca gagcagagct 13860tgatttgggg accagccgag ggcagtttgt caggattccg gcttgaaact gttctcacat 13920ctcaccgcct gaaaggacga gtgtgtccag aggacttagc attgatcacc tctgtctcca 13980tgcagcaaac tcagaggctc agcccgcatt ccactggaag ggcgtttgcc agtggtgttg 14040gttggaagag ccttgacttt gccttaggaa acatcttttt ttaagaattg aaaataactt 14100gagtatgcaa cagtagggca tttgttatat aaattagttg actagtgtgt agccagtaaa 14160atgatgatgg tggtgtgtat ttgttaaata aaaagatatg tgtggtatta aattaaaaaa 14220tattttaaaa caacatattt gtaatctgtt tagtgtcctc tttttgtaaa aagtacagaa 14280ataaatatac agaaaaaata gtagtcctaa gtggtagaaa ttatgagcat tttcttgcct 14340ttaaaaaaag ttgtaaaaga ttgtatcatt tatgtagcaa aaagttttaa gtcagcattc 14400taaaaatttc gtgttgttat agttgctgtg acaagattta acttctgtat gcttcaccaa 14460tcaatacaga ggtatttaag acccggtgtg tgataggccg cgctaaaata ctatacacat 14520cttcagaaaa ctagagaact aacttctaac ttcctatatt agtgtggcac ggctgttaca 14580aagatttttc tcatttgagt ctatcttgct tctttatcat tgttttgaca gtttcagaag 14640aatcgtggct tttccccttt tttacagtaa aggtacctga gactcttgac gtattgcttt 14700ttggaaatgc ttgtgctggt cacatgcttg catctgggct agtgtgtctg gcttccgtgt 14760gctggtggat gcttactctg ttttctgaaa tactttttct gtacagtggc cactagctgt 14820actcctaagc cacacaccta ccttgaaaat tcatgtcact tttagaaata gataaaagcc 14880cctcccatcc agaaaaagtg actatcatgt atatcctcat catgactaat actgatattc 14940ctgaaattga aaatacatat tccatatgta ccataaaagg tattaaagat atatggagtg 15000atagatatat tatatataac acttctaccc tcacagtttt cagcctaatt gagagggtaa 15060gatccctgaa tcatccatca gtttttcagg tctctgctga aagcaggcca cagctcagat 15120ccacacatct gaaccagaga cagaggtggc caaaaataaa aagggggaca gggggacaac 15180ctggtttaga gtcaacaaat agactgcatt ttctggttag tgaaggagct ctcctgaaag 15240tcatatacca gagcataaat gagcagattt ccttgaggtc accttctgct ggccatagct 15300ttcttatctg tggagctgcc agctgtcatc cactttgggg cacctgagac tgccgagcgg 15360caggccagga cccaagtgcg aaaacacaga acaccttttt gtttctactc cactgatgct 15420ggggttctct ccctggtgtt tgtggctcgt agtacactct gtggaacatt cactatggtc 15480atcgaagggc agcatcttcc cagttgtttc tttcttttct tttttttttt taatttaaac 15540cgatctgaga agccagccat ctgtcagcaa aacaggaagg ctcgggctgt ctcctgggct 15600cgttttgctg ccgtagtgag cgtcacttct ccccgtgtaa gagtgctggt gaaggctgag 15660gcaagggccc agaaagattg agggacaaag acaggagcgc ccgcattgcc catctgccag 15720gctggaggtg tattcattat tgatggaggt agtgcagttg ctgctcagat atgcagccct 15780gcctgggtaa atgagacatt cttcagcaaa ttgcttcgtt ttttgattgc tgattgtacg 15840cgtgtcacca agctgactca aggttcatcg atgcatgctc agtaaattag aaagaacata 15900actatggatc agccaagaga atgaattctg tgcctacaat gacccagggc catttaattt 15960tctgcttaat tttgttgcag tcagtttgca ttttgggtta ttatgcagta ggaaattaac 16020aataaataac aaatttggtc ctcctgtgct tgtaatgata tttttataaa tctttgtaat 16080gctgttttta aaaggatcaa ggtctgtgcc agtctgatac tccagcaagt atgtgaggag 16140gaaaatgcat tattcttgct agataacctt gttgttaaat agcatagggg ttctttatct 16200ctctctcttt ctcatatctt attagtattt ttgctttaaa ctaaaatccc ttcctctctt 16260tctcagataa cctgaggacc atggatgctg atgagggtca agacatgtcc caagtttcag 16320gtgagacctt atgagatagc tgtgtgggaa gttcatgaga aaagcttccc tggggccgga 16380agtcacagtg cttggtatgc tcatggggga ggaatagggg ctattctgca aaagaaaaga 16440ccatgatgga atttgcctga gtgtttcctt cacctgttac aaattatctc actttgagct 16500gaacagaaag cctccaagat gaaattagtt ttactgttaa acttcaggaa aaaaaaacgg 16560gaagagttaa atacattttt gtactgttgg aaggaaaaat ggctgattgg tttaaaaccc 16620aaacacatgc caatgatggt acttaaagag agagagagag agaagcttga aaaacataat 16680tgttgggcac agtcatgact gtttgttcat taagcatgga cacaacattg ctcccctttg 16740ccatatatct tttcaagccg tattggatat agctcttctc atccaggaga cccaggaagt 16800ggagaagtct gtagtaggaa aagcctaagg gtaggtcaca gactgtgacc atttggcagc 16860actgagggtg gacggcgagc cagtccaaca aaaccgcaca gttccccagt gcatggacat 16920aggaagacag ctttctatct ggccctgtat ccagaggcgt cagccccagt agcagctttc 16980atggactttg gggttttcgg tatttcatat ttttgagcct cacagactca cagccagccc 17040cagaggctga cttatatttg agaaagttct cagtggcacc ttgccttggc tgagcgccct 17100cgtgttttga agtttctatg ggattctaca agttggtgct cctgatgaag accaggacct 17160atgtgtggct gctcccctgc ttggtggttt ccctggggaa ggtgcaggag aggatcttct 17220gagttccatg gaactggaga tagatctgcc aatcacaggc ttccttctcc accactcctc 17280agccgctcta ttcatgtttc agattttgga cttaaactct cccaggtgca aagaacaaac 17340aaaaggctag cttatttttc ttttagagtg aggcttcgta tttattacaa tataattgcc 17400acattctttg tgtaattctc acatttatat cttaaatata attctcatga atgagaatta 17460tataattctc tttttgtata tcattgaata ttttcactta atttttaatt tttttaatcg 17520tcacaaaata attgtgtaca tagacacaaa ataattgggt acatagtgat gttgtgatat 17580atacaatgta tagtaatcgg atcaggtaaa tcagcatatt catcatctca aacatttatc 17640gtttctttgt attaggaaca ttcgacatct tccttctagc tatttgaaac tatatattat 17700tgttgactac agtcatcctg caatggtgta gaacactaga acttattctt cctacctagc 17760tgtaattttg tctcctttaa caaatctctc cctatcttcc actcccccga cctttccagc 17820ctctattagc ctctgtccta ctttctactt ataatgatga cagcagcatt tgttagtttc 17880cacatgtgag tgagaacatg tggcttttta acttttagaa tgtggtattc aggcacttca 17940tggtacagtt ggtaaaagtg aaaatgtgtc caaaagtttg tgattatcta tataaacaaa 18000aatggtataa atacaaatat caattttgca ttgaagaact taccttagag gtatattctc 18060acaagtgcac agagcattta agcatttgtt cactgcagca ttgttatcag tattttaaaa 18120ctatggtaca tccatgtact tccacataca gctcttaaaa ataaggagga tatgaatgaa 18180ctagtatgaa aagaagtcca aatacatgtg aaagtgagaa tagcatggtt ctggatggta 18240tgcaaagtat gatctcgttc ttttaaaaga aaataaatta catacacata catattttct 18300atatgcttgc ccataacgtt taggaaaatt cttgggtgat atttattaac ctggacttcc 18360tcttggaaga ctgatggtag aaggaagggg acgagttagg gaagaggagg agaaggaaaa 18420ctttgctttt catcttctac cttttagcat tatttgaatt tattttcctt aagcgtttac 18480tttgtttcgt aaacaaaaaa gcacaaaaac aaaaaacgag ttaaatggga aaaaaagcag 18540tttagctctt tatagcctct catttggctt cgccagcctc tcactgcagc ctcagagagc 18600tggtctggga aacactggta gatgaggact gtaatcctca ctcatggaag aggatctcat 18660tcactgggtt tgctgactgt gactagaagt gattagggtg tcaaaaaacc caagcatgtt 18720aaaaatttcc agaggccaaa aagatgcttt cattgttctg ctcttctttt ccttgtcgct 18780ttcactttgg gtagcttcta aattggtatt ttgcatggtg catttaaaga aaatgagacc 18840cctttggcca atgcaggagt ctacactctg atattctaga gtcaaagctg aatgctgaca 18900cctaggaatt catctctaga atgtttatat aaggaatagc ccctcagtat tccgatctcg 18960tatcttagta acgaaactaa caaaagcctg attctcctct ggtagttttc ttgtctttac 19020cataatacaa aataagtaat ttgttctgca ccctgactgt tcaaaggata gggtagctgg 19080gggcggggac aagaatggag accttattac ataagacttc ctgaaaaagg aaactctgtt 19140tttgtttgaa atgatttggt ctgaaattta gtttgtgtac acttaccaaa gggattccta 19200tttctaaaac actcatactg cttttgattc ctgttaacct ttgagcactc tacgtaatga 19260tgagagcact taaagagtca tgtcactttt agtaaagaat caaaggatac tttttctact 19320tcttcgagtt tgatctctgc ttctccagtt aaaaccagta tttgtttttt tcatttctaa 19380agttggaaga aatgacagtt agttatggca taaggatgta catttaacca aataggagtt 19440gacattcttg gtaagaaatc ttaccaagat tatgttatag attataagaa atcttaacaa 19500gaatatgttc ctaaatcatc ctcttttccc ataaaatatt aaagtatcag caatttcata 19560ggattcaacc taatgtatgc gaaatgctag ataaacagat aaatacttaa tatctggctt 19620tttttcaaag cactgggtta tttgttcctt gagatttatc ctaaatgtgg gctataccct 19680ggtttacagt gtctcacaga tgtgtagtag tagacactcc ataagtgttt actgacttga 19740atccacaggg tactgagaaa atgctactga tagacttgga ggagagcata tctaaagcaa 19800gctacccttt cctttagggc acgtctcact aattctttgg gtaaagcgta tttttcttcc 19860ttttgtgttt ttggcagtct ttccaaaaat acgtgttata cctatgcatt attttttggt 19920ttggtttcta aagaaagagt cagccggtgg gaaagtgaag gatgtgggaa ctgagagatc 19980tgcatcagca tcccacctct acctcccacg atgggacctg agacagttat ttttgcctcc 20040tggaccacta tagtatcatc tgtaacagga gggacttgag ccagttgatc tctaaggttc 20100ctctggcacc tgtgacccta aatagatatt ggatattggt ttaatgctat ttgtagtgtg 20160tttttttggg gatatggaaa ccagaagttt gtttccataa acataaacat aaactgtata 20220tatctaaagg atatggaaac ctttagatat atataatctg cttacgtaaa gaaggtttgt 20280atatattgca gtgtcaatgg gaatatttta tcaagttaag catagtaaat cacattgatt 20340aaatgctttg tatttaccaa acattaccca aagtgttttc tcctttcaac ctcacaagga 20400cccacagaag aaaatacagt tatcatttcc aacctgcagg gagctgagac acagagaatt 20460taagcaactg accggaagtc caacagggag tcagagattg ctctggggtg tgatccccac 20520ttggacccta gagtggaagc ttctccacta ctttatagag ttgagattct atattttgag 20580cttgtattta cccagagaat tatatcctct tgggcaattg tgtataataa aacctcatgc 20640atttaggaga ggcgggatga cagaactttg ttgagtgaat tataatctac

ttgagaaatt 20700atttgcttac attttataag ctaattatac catatctcat ccagttttcc cagaacactt 20760ctcataggta atgctttatt tgaaacatag gccataggta agttaagtgt aaatgtgtat 20820ttttataatt taaccagaag tttatttcat ttttctaaat aagtgaaatt gtattgcatc 20880ttctaaatta ttctatttaa acacttgatg tcttgctgtc tccgtctctg tgtgtttgca 20940tgtcattgta catgttctta ggaaaagtgt gggagcttga cgcaatatat accttatgtt 21000tctatgtgca tatagtttac caaataatac cataagttta cttagcatat tagaatccat 21060gcacattatt tttattttat cttcaccgca accctgtggg atagaccaaa atcatgcttt 21120tcagcctcct ttttccactt gaggaaagga gtcttaaaaa agggaccagt ctcatgttcc 21180cattcgtctt acaactaatt ggtcaagcca gaaagccaga actatgtcct gggtcactaa 21240ctcctagtca ctgtgtgtta gtatttgaga tgcctgttgg cttgatttag tcatttattt 21300tttagtgttt tataatcctt gcatactttt acattttaaa tggttaacca ggcaaattgg 21360tttaaaatca gtgcataaaa atactgtgcc tatcatgatg ggtttcatga agtgataact 21420tttcatcatg gagatcctca gctgtcacag aagatgaggg gccctgggta cagaggctca 21480cgtgagggat gaaagtctca gcagcccgga cttacacttt ggggctttta ggcaaatcag 21540acaacctctt aagaactatc actgagttca ggcaaggcga gcttgaatta acacagggcc 21600cttggtgggc atgtgaatat atctcacttc actaccatcc agttctgact ctttactaga 21660tgcccctgta cataccaaga ctgatttttt attctccctt ctccccatgt ggtttcttct 21720gcatagagag ttcctattga tcagtctgac ccatggtatt ttagaattgc gatccctact 21780gtttcattat tcctttttct cccccatgtt gaaaaaaata aatgtcctga gatgcaagat 21840cagggacact ggagcactga catttagttc agtgcaggaa ctgaaggcag atgtaattct 21900taagaagcgt acctgttatt atgaaccatc ctcaacaaat tgtagtggat cttgttttct 21960catagataca gcagttaaat tttttaataa aagtaactaa gagttatttg gatgtatttt 22020agcatgcact gagcggaaag tacgacattt cttcattggg taagtcctga ttctttatga 22080tcctcacttg gttccagggc cccatgcatc taagggtgtc tcagagcatc ctgcagtgct 22140ccagcatgat cgcagggaaa agctatagga ggaaaagagt caataaagtt tagtttctca 22200acctcccacc tccaccccat aataatgaca gctggttaat catgagacgc gtgcacaccc 22260cacacgccct gtacatgttt actcattggg atagcatgtc aggccagaag gctccatggt 22320catttctatg aaggtacttt agcaggtctt caagaaggca agtggcctgg gtccctgcct 22380ccccaaattg caagctccct gctttatgta ggagacctat gtgtatatta cagttctgtg 22440taagattatt ttgttattct tacccccaca cccacccccc aaccccccgc tgccaccaaa 22500aaaaaaaaaa aaaaattcct ctgacaacct tcataaagtc ctgggagttt gaacaccatt 22560gctctaggaa gtcatcttat acaaaaataa gagttgtgag gtggttcata tacctcctgc 22620gttctcctat ttggagtttt tccccattta tgaaagaggt gaaaacgcta agatatttag 22680caattattac tttaaacatt ttctatttat aggccgggcg cagtggctca tgcctgtaat 22740cccagcgctt gggaggccaa ggcaggcaga tcacgaggtc aggagatcga gaccatcttg 22800gctaacacgg tgaaaccctg tctctactaa aaaaatacaa aaatttagtt gggcatggtg 22860ggggatacct gtggtcccag ctactcggga ggctgagaca ggagaatggc ttgaacctgg 22920gaggccgagc ttgcagtgag ccaagatcgc gccactgcac tccagcctgg gtgacagagc 22980aagactctgt ctcgaaaaaa aaaaaaaatt ctatttacag cagtgaaaat agtagtgact 23040taatgcacat tgccaaggct ttagcataac atgaacactt tcactcaatg tctctctggc 23100cttttgtttt tccttgggaa attcttataa tcctgctccg tctttaacta ttcattttgt 23160attggctatc caaatatacc caataatgct ctttctgaaa atatgccaat tgtggtaatt 23220acagctaagc tggaatatta aattgtgatg tctgttttcc agagaatgaa gtagtattcc 23280ccagagcata ggcttggtgc ctgtgcaggt tctattttaa atattccagg aagggttgtt 23340ttatatactg aggatgattt tactggtctt gccagtcgtc tgaaatgctg gtattactct 23400tgtggaaggt ttattcaaac aaacaaggac atttcacaca atacctagtc atgtttttca 23460gacattttaa tgtttggttc atcatttgca cacactctca aaaatctagg tttgtctatg 23520tgttcatatc attttgcctg ttgccagctc agtcagcagg cacactctcc caggctgttg 23580ctgttttgtt agacttcttc aggaccttca tctaaaatgg tcttccacac gtagctatac 23640tgcataagtt cacatcatct gtttcttgca tgtgggttgt gtctcaactc aagtttaagt 23700tagatttgga agggcggaaa ctataggagt tgcagcttca gtggagaaaa gagcatttcc 23760tactagttat ggcttcccaa ggaaggttag attcctcaga gtaggagtga ttccccaatg 23820ctagaacctt tggtcaaata taattctaat ccagtcaaaa taaatacagg tattctgtaa 23880aacccgattt cattttgtaa atcctacttt gtatagtata agcaattttt gtatttgtgt 23940ggattatatt ttattttcct atttcaaaga gaagaatttg tattagcaga ctccctttgc 24000atgcggagag gggatcattt tcccagtagg catggggttc ccttccattc cttgtccagt 24060cttcttttcc ccactaagtt aagtcaaact aagcagctgg taagatattc cctggttctt 24120gcaaagaaag tgagcagatg gcagaatgta tagctctaag cagaatacct ggtgtggtat 24180cctcaaacac aaattgacag gagggtgtgg tgtggcaagc tcattgtggg ggtaaattgg 24240aataagctta cagggggaag agttgacaaa agataggaag aaccttaaaa atatagatgc 24300cttttatgca gtgataaaat gtctagatat ttatactgtg gtgattatta ggaatatgtg 24360caaagattgg ctattaggat gttcattaca gtgttgttta ataattataa aaggacagaa 24420agcaatgtgg actcaaaaat aggaaaagaa tttaaataaa tcctagtgta cccgttatac 24480atgaaattat ggaaatatga ccctgagcat ggaaatatgt acatgagaat gtctaaaagc 24540tagttcattt tgaaaaacaa aataatgtca cctcatatta tttatagtat ataaagatga 24600ttttaagagt ggcagtgtct gggattatag gtgattgtat ttcttccctt ttgcacatct 24660atgttctctc atttgtattg tgtggggaga agtgactttt tttataaaaa gaaaaaggta 24720tatgcatccc agcagagaag cactggctcc acccagtacc tgcctcctca tgccaccctc 24780tcaagccaaa agccggggga agcccaggca ccttgaccat gaccgcccga gactcacact 24840tcttctttct catcagggaa ggaaagcccc cctgtaagcg atactccaga tgagggcgat 24900gagcccatgc cgatccccga ggacctctcc accacctcgg gaggacagca aagctccaag 24960agtgacagag tcgtgggtaa gtgggtcacc agcggcctct gtgcctgtga aacctttatc 25020tctttgtatt tttccaagac agtgatgaag ggatgcaagt cattttatcc attgtgttcc 25080ctcaactggc atattaaaga aatatggcac aaagatcagc aggatggggg tcctctggtg 25140tgtgggagga tggacactca caggccagca tggccgtgag agccacacac cccgcaaaat 25200gtccaagttg aggagcaatc ctgcccaggg acgcgtctct gtcactgtcc tctgtcctca 25260ctgcacttgc aggaatatca aatgttatgg attgtagatc gtgaaaatta cacacttacg 25320tgttttggca acagtgcttt tcagtgtttg gggttagaac aagccacatc tggccatttt 25380atgttatccc tctaatctct agttcttaaa tttcagattt aactgaaaat agaaagtttc 25440ataaatggta atttttaaat gttagaaaaa aatcaaagca cacatttaca taccttttcc 25500ataaaaaagt gtgtgtgaaa ccatctgcaa ctccactggt taacttacac atgcgacagt 25560ttgtgtttgg aaaacttcac ccaccctctt tatttcaaga aaccaaagac ggagagaagt 25620tcagtgaatt aaccaaggtg aaatgacaga gtcagaattg aactgaattt ctgactgaaa 25680aactagttct cgctccatta taccatgttc taatgagcta atgagtcaac agttccctgg 25740aatacctgtt ttcttcttta aaaagagaaa gagctgtgat actgagagct acctattggc 25800ataaaagaat atgaaggaca tacaggtaaa atgaggtaga ctggatcaat gtgggtcagc 25860tacataagcc cccatagcca aggagggaac atgtatgtaa aattctcagg cttatgagaa 25920tcacaactgt atgtctatag gacatcctaa tgcaataatg ggaaaatgtg ataactgaat 25980tttatctaca tgtatagaaa acatattttg ggccgggcat ggtggctcaa gcttgtaatc 26040ccagcacttt gggaggccga ggctggcgga tcacaaggtc aggaaatcga gaccatcctg 26100gctaacacgg tgaaaccctg tctctactaa aaatacaaaa aattagccgg gcgtagtggt 26160gggcgcctgt agtcccagct actcgggagg ctgaggcagg agaatggcgt gaacccggca 26220ggcggagctt gcagtgagcc gagattgcgc cactgcactc cagcctggat gacagagcca 26280gactccatct caaaaaaaaa aaaaaaaaag aaaaagtaaa gaaaacatat tttgtatgtt 26340ttttatgtgt cttagaaacc aagtggacta ggtataatgg ttcttttttt ttttaactca 26400gcagcacagt taatggcaca aacagataaa gatggtggct aaagccattt ggtgtagatg 26460aatccagaaa acaagtacat ttatgaatta ttttacccta ttggaaaatg gctactatat 26520gtggaaagta gaggggaaga gaaatgaact tgtgaattat ctactctatt ctaccaaaga 26580aagatacata tatcatttca gggttttcca aagttgggat gcaaaggatc atgtttcatt 26640ttaatttatg tatttatttt tgagattgtc ttctatgtat tgcaagtgat actggtttta 26700ccatgcactg taccactacg agggttcctt tcaaaacaca ttcatataaa ttaaaaaatc 26760agtttaaata aaaacatcaa gtcaatagta gtacatagat atgataaaag tttgcaaaag 26820tggcacagga atagtcattg ggtggtgatg ttccctgatt tttttagtcc ctgaagcacc 26880cagcgccaag ggtactgttc ttcctgctta acacaggagc aaacagatgc tcacaccctg 26940cccaagaaca cagaggctca gggactgaac cagaagaaat gatccattaa ccatgtaaat 27000gaacagagag cctggatgtc agagtgagga ggccagctcg ggtcgctgtg gagaaagaga 27060tgggctctcc ctggaatccc tgcagctgcc cttagaggct gtgagccatc gtggctaggg 27120catctttaga gaactgaaag tcaggccgat tcctggagag tgaagaatag cacacgtgcc 27180ttcaaaacag tgtcagtatc ctgtccctta cggacgtcat attgttggtg ggttttcctg 27240ggtgggagat cacccagtat ctggttggca ttactgatgg gttcccagag ctgtcttttg 27300gttcaaagtc ctgccctcgg tcccagctgc ccccagcaca ggtgtcacct tggagtcagg 27360ggcgggtttg tcatagccca tgggtcctgg ccctgccctt tatcatgttt gacatgattt 27420tcagtctact tttccttcag gatgtaattt agaaaatatg atttcagaat tgtgaaattt 27480aaaaacccta gaaaacctct ttgctttgct tgtaaatagc agttgatgca gccctgtgga 27540caggcgggaa cagccatgtg acgtgggcac tgagatgatt tgggagattg aatgctcctc 27600agtggggcta gaggccacag gagtgatagg ttactgtaaa gaaagcaaaa aagatgcaaa 27660agcctacatg acaaaccagg cacgacacaa aggagaggct tgagaagagg aagtgaagga 27720gggagaggat tccacaagac cgaagtgccc aaggagacat ggagggaaga gagggctctt 27780cacagagctg agtttagaga ccaccctcca tggttctgga aggaaaccag ccagctttca 27840tatgtggtga caggctgttc attaatttgt agtgtacagc attaaataaa tgaagtatgt 27900agagaacatt aggaaacaat ataaaaaggt aggggaattc gtggataaag ggaataacct 27960gggtaccata tttcatcaca ttattccatg ggaataagtc atcagtgcaa aggactgtaa 28020ggagtgcaca gcaggaaatg aaaagacaga agcagtgggg ccgagaggag gaaatggagt 28080tgctgaaatg cagggtgagc agcaggggcg gagagtgccc tgtgggtaag gcacacctca 28140gaagggacag gtccaggccc tctcctccct ggcctggagc ttctggcaag gcttttcttc 28200tctgagcctc actttcctct tttgaaggtg gcaatagtaa ctgaacctgc atcannnnnn 28260nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 28320nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 28380nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 28440nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 28500nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 28560nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 28620nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 28680nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 28740nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 28800nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 28860nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 28920nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 28980nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 29040nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 29100nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 29160nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 29220nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 29280nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 29340nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 29400nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 29460nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 29520nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 29580nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 29640nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 29700nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 29760nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 29820nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 29880nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 29940nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 30000nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 30060nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 30120nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 30180nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 30240nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 30300nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 30360nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 30420nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 30480nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 30540nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 30600nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 30660nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 30720nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 30780nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 30840nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 30900nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 30960nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 31020nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 31080nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 31140nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 31200nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 31260nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 31320nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 31380nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 31440nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 31500nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 31560nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 31620nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 31680nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 31740nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 31800nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 31860nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 31920nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 31980nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 32040nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 32100nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 32160nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 32220nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 32280nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 32340nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 32400nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 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nnnnnnnnnn 65100nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 65160nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 65220nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 65280nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 65340nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 65400nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 65460nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 65520nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 65580nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 65640nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 65700nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 65760nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 65820nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn

nnnnnnnnnn 65880nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 65940nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 66000nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 66060nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 66120nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 66180nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 66240nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 66300nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 66360nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 66420nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 66480nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 66540nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 66600nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 66660nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 66720nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 66780nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 66840nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 66900nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 66960nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 67020nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 67080nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 67140nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 67200nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 67260nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 67320nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 67380nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 67440nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 67500nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 67560nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 67620nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 67680nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 67740nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 67800nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 67860nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 67920nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 67980nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 68040nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 68100nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 68160nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 68220nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnaagctt tgattgggcc gttactgtct 68280tttgaccttt cttgtttgct tgcccttttg tttctttcct cctttttcct tccttcctgt 68340ctttcttctt ccttccttcc tttcttcctt tttcttttta attttcctcc tttctctttc 68400tcctttcttt ccttccttct ttcctctttt tttctttcct ccctccctcc ctttctttct 68460tccttccttt ctttcttccc tccttccctc cccaccctcc ctcccttccc ctcgtctccc 68520ttcccctcgt ctcccttccc ctcccctccc tccctccctt cctccttttt ctttcccttt 68580cctccttcct tccttcctct cttcttttct ccatcccttt cttcctttta acatttgatc 68640atgggtacca tttcatcaag attctgttac ttaggtccaa ggactagtga ccaaattgtt 68700tttcccagga gtaaactttt ctacaagaca tagagaaatg actgccagtg ccatcaggca 68760caccatcctg tgtgataggt aacctaaaat aatggtacag cggggagtaa ctggaagagt 68820cacaactaca caaatctctt gcattttcct gatcattaaa tgaattaggg atttcctggt 68880ttgagatttg tggacaagga gaactacttc tttgtacaag aggcttgtgc caggagaaga 68940cacgctgtgg ttacaatgtt actgtctcta gctatggtca tttcatgtct ttaactgagt 69000gtacctagag tgtaatacag tgcagcagtg atgggctgaa ggcctaatgc accagcacac 69060atgcctggaa gacctaacgt tgagaatccg catttttttc atcactcaca tttattttgc 69120atctccctgt tttgattacc ttcagagacc caagcacttg cttttgtata tttgagtctg 69180ggttttattt tccttttaga aatagtccaa aatcctttta gagcctagac ctttgaataa 69240agtgctaact taacctgagg aatgctgttt ttttgttcac aaataaggct taattgtgaa 69300gtcgtgagaa ttgctttctg agctgactta taaatttacc cacctctttt tccccaaacc 69360cccaaaaaat cctccagaag gtgagcccag cttgttgtaa aagattttga agcagaagtc 69420ctgggtttaa gcttcagttc tctgccttac cagaatcggg atgtgtgggg caggcctacc 69480tcctctttct tcatctgcaa aatacattga atgaaatcat attttttcct aagtatatga 69540catgtaaagt ggtatttcaa aaactcatta atctgcatga ccaggtcaga aaagacacac 69600cttttgcctt gtgtctagtg tgtgactgtc ctcacatgta gatgacccag gccacatccg 69660ctgatgttgt cttcctttac ttctttgtcc cttccaatga ctcctttatg aagtcaatca 69720gcagtgtttc taagccaggt tccttctctt cacacatccc caacccacag ggcaagtcat 69780ccacattttg cctctctatt ttttgtgctt tgggaaacac attttacaac ttccaaacta 69840tttgcctaag ttcatctgag cacatctaga attattccac tcctctgcat cagtgctaaa 69900agtacaatca tgtataagct gttatactcc cgttattttg tacctcatgt gcaggtagat 69960tgcaagttcc ttgcaggcag gtactacatc tacttgaatt gcttcacgat cacataacac 70020aatgcagtgt taaaagtaga aaagtaattg acatcttgac taacagaaac actaaattca 70080gtgtattgtg atgatacctt tttaagagat aggctataga aatagaaaat catcttagtt 70140ggaattgaaa gtcaagaagc aacattttaa gtaagagatg aaaatactta aaagggaaag 70200gagcagtgct tacacagatg aggggaaaaa ataaaatgta tcatctaaaa atttaaatca 70260aatatattag gttggtgcaa aagtaactgc gatttttgcc attaaaagta atagcaaaaa 70320ccacggttac ttttgcacca acctaataga tgggaaaaat aagaggaatg aatattttaa 70380gctttgctat ataattaaaa tattcttaga agtctggagt ctgtgaaggt cacaccctct 70440ggtcttctcc cagcccatag ggtataaata atctgaattg acggcatcca gggatctcag 70500aaattattag tacatcccac agtgaattac caccttacta aaatattcat gggtatatac 70560tatggatttg ttttatccta tttagtctta aaaactataa agaaatctgc aggcttatta 70620acatattact cagaatcata ttgtctccaa agcacaaact gaatcagtta caagatattg 70680gactagagat catggcaaat cagaggtaca taagacctag ttccgttgtg gagctaaaca 70740aactgcagag acctaaaggg aagccttgca ccacactcta ggtttggagc tcaggttttg 70800agtggtgtca gcactccaga acacatggga tccccgggag gtggaaattg agccgtcttt 70860ggagaatcag ctaatgagac agatgcatgt taaatgtctg ttgtggccca ggcactctgc 70920taggcagagg ggtgaaccag aagaatgaga ttcatggggc caaagaattt gccttctggt 70980gtaagaaaag atggaggcag cttggcagaa agaaaaaaaa ggtaaaagat agaaatgaaa 71040tacagaataa tctatctcct catcccacaa gcaattctgc ctggtttgtg gctcacgcct 71100gtaatcccag cactttggga ggccgaggca ggaggatcac ttgaggtcag gagttcgaga 71160ctagcctgga ccacaaggtg aaacctcatc tctactaaaa atgcaaaaaa atttagggcc 71220gggtgcagtg gcagttctgc ctggtttgaa catctggttc agttaaaata cttcatgaaa 71280atatttagct tgatgcactg aaatccatca ctgcttttgt gggatgcact gactgcagtc 71340tgactgttct cctagtggaa aggggagcaa tagcttctgt ctgcatgtgc atgaaacaga 71400tggaaattta gaagagattc tagtgcagac aacttcatcc cacccccgct gcccacagag 71460ctagccatgt gcacggtgtg tttgaacaat gttatgttgc tgctgtgcac agagatcccc 71520agtctcataa aacatactgg atggaaggct gtcgagagat catcaggccc cagtgcataa 71580gttcttccta agcatcctta acaggtgatc acctcgccta ttgagaaccc tcaggaggca 71640gcccacttac ggaagcactg attgttacaa aagccctgaa ctaaatctgc ttgtctctaa 71700agccagccct gcagatgtct gcagtgtaac tactttctct tctctcaagc agttcagccc 71760ttcaaatcat tgacaacagc tctacaaagc cctctaaata gcccgttctc ctggctaaag 71820tgtgttggtt tcctcagcat atgatgaaat aaacaccatg atgcctttgc cttgcttttt 71880cttgctggtc tcactcttcc ctggcattct tcaatgtgcc caagtccttc ctagaacatt 71940gcacccaaag ggccttcctg gtctttccag ggaatgcaga atgaaaaaga aatcccatcc 72000cctgcctcga aaggagctct tctgtgtgta agtgtacctt ccccctcagg gcataatggg 72060aaacagtttg ccaaagctaa ctgtgtaatt tcacatgact cactgccgtt agtctgagaa 72120agcatggcat attaaactca ttttccatgc ttcccaactt tatttactat tccatttctg 72180aggggcagag agctgagcag gaataacacc ttccttgctc ctcctaatgg ggcacatgtg 72240cacatataaa attgtgttcg atctttgcag ccacgaccca tgttaactgt caactgagaa 72300ctcatgagtc agtttctcag gaacagccct gaagacatta tctcctgcat cttgtatttg 72360tgcctttgat atttggaggg aagggtagga tctggcaatt atcgttatct catttggttc 72420agtgtatttc atttcagcct gttaagatct tttggaaata ctgtatgtgc tagttacagg 72480gacagtgata aataagacag cattcctgtc cttgagatgc tatttccaca gctccatgag 72540atgcctagtt aaaaacagag ccttttttgg aaacagccta ctaatctgtt aaaataataa 72600tggaaaaaga taaagttagc atacctgagc tgcaagggct gcctcctggt ctgatctctg 72660ataaggatca gatcctagag cctctgagat ccctgtcctc cctgtctgca caagcactcg 72720cagaaggaga aacagtttac ggtggttcat catgactttg aaccaagctt aaagtcaaag 72780tcatactctt taaaccattg gaaaccaagt ttttgcgagt tgcctaaagt gggcaaaaat 72840cccacaatgc acctgagcac aagcaggaaa acatgccatt gtctccccag gagccctcct 72900tgacttctac tttactttat ccattgacac tagtcttata agtagctttg tctgtccaat 72960ttttaattga atttcgtttt tattttcgtg agtggaaata tcactttgaa agaaatcagt 73020cctctcctga aatccagaat tcctggagct cagtttacat gtttgacgcg tgtcacatga 73080ttccacaagt cactcaaggg caggaggatt accatcgata cggaaagatt tcttagaaag 73140cttaagtgaa agggaaacca gggagaaagt gtgcttcgtg agaataggta tgcggacggc 73200tctttgtgac gctctgtgca accctcgtgt ttgcattgaa ccaagctgtg ctgcagatgg 73260acacccatcc catttccccg actcatacca gggaggccca ctttgcaagg tacacagagg 73320ggaccacaga gcagggggcc atgcagggga ccaagggaca ttttagtgta accaaagtgt 73380gaagtatgcc ctttatttca aaagaataaa gaaaatcaca ggttttcccg ctgatatgcc 73440agggacattt ccaagagaat tccttttttg agagaaatct cctttgatat cccatcagtc 73500agccatactg cataattgtt agatagtgaa agaaattcat tttttaagtt tgtcagaaaa 73560ataaattctt tgaagtctta aattgttgcc tccggacatg acatatctgg ctcttccaga 73620atccatgtta gtcctagctg aggaagaagg agaaggagag gggcgtttgt tgattattga 73680ttttgtaaga tgccccacac gttggctatt agcagaattc tcacttctaa aaggaaaatg 73740agtgtgagct atgttcaatg agaaacagtt atttttggga cattctttga ggtaaaacac 73800ctccttaaga tgctgcttcc ttattgctat gggaccaaga ttagagcaag aacatagtgg 73860ttttcagacc ctggacatca tccacagccg cagcagaggc cctgcccact tgaacaatga 73920gacaggccac cattttgttt cgagaatgag caaagtgaac caccatgcca gatattgtta 73980agtcagcaac tcttctgaag atggacatag taaaaaataa acaaacaagg cagcacttga 74040gatggtcatg gcagagcaat ctcaacaagc gatttgttat tttgcacagt gatgtaccca 74100ctcattgaat aaaatgcacc agaaccatgc actacagatg ctaaggagag ttgtccttca 74160acaaaggaga taggccccac tggccgtggg gcagtttatg ttatttggtc cttgtcatgg 74220gcaggcatgg ccctttctat gcttcacaga tgaggaaggt ccctggcaca ggtccagtct 74280ccagcatggc ctagaggtgg caggtgctac ttagcatcgc cagcctcctg cttggtcatg 74340gggtcagcca gtttataaca cgaacggagg ttaatgaact gatcttccca tcgcacaact 74400ggtatgaacc cacatcttct gattataaat cttttgctct ttaactctta gtcattacca 74460ctgtctagtg taggcctgtg tgttcatggc ctttgttgcc accaaaagat caactattag 74520ctgaataaca tactgagaca tgttggtgtt gtgttctaaa tagcactagt aaactgttag 74580ggaaatctga ctatatagct actatccagt ctagtttttc ttgcgaagtg tttgttgagt 74640gtgtaatgag gagtaaggaa ggtgaataag aaatggcctg agtctttata aaataagcaa 74700ggagagaaaa cagttttgat gagaagcgca tggaattttt agaagatagg acgtgtatta 74760tgtacctata agaatgggta ggattttaga agagatggat ggggaaaagg aacagggagt 74820gggaacaaaa cgtggaccaa ggaagagcag gtttagccat ggaagcctca ccgccggctt 74880tggtttatcg tgggccaagg ggacagaccc tgtggggagg gctggcagca gggaggtctt 74940ccagaagtct atcctgcagg cagtaacagc cacccagtct ataagctgag tgggcatggg 75000ggtgatgggg aatgggtggg gagttattgg ggtaacttac cccaaaatga tagctagctg 75060gaaccattta ttctattgca ttttatcaat aaatcttata ggaagtacca tcctagtgaa 75120aaccctgtca cattgagggc attcatgctt atgttttaaa acatgttatt gggtctatga 75180aaaataaggc tgaaacctat gagcaccctc catgcaaagt ttcagtcaag actttggaaa 75240caagacagtg tcttactcac tttataaatt cattcagaaa gccgtaggtt tgaaaattcc 75300aaacttagat gtaagaagct ctgagaaaca catgaaatca cccccacatc agtagagatg 75360tctcagcaga catgggaaga ggggcagcag ggtgtaggga ggtggggcag ccccggggtg 75420ggccttgcag gctgggcttg aatcccatgg ccaccaccgt ccgctgggag gcctggagcc 75480ggctgcccac tctctgacca gcacatgttg atgctgtatc cttgaaggga ccgtggtctg 75540acatcctgtg atgcagacct gaatccagca cccacagggt ctgcacattc cctctttgag 75600gtggagccca gctccagagg ctggtccctg actctgtttc tcaagaagcc tgtacagatg 75660ttcccctcac cactgtttcc agtcaccttt ggctttcacg gtgcagatgc taagtttgat 75720tttcagagcc catctgggaa tttagtgaac tgaacaggta gcatttctga acccacccat 75780aacccatgcc ctccccactg attttgaaag agagtttgct gcaggtgact ttgcagctgg 75840gtagagaatc ttggggcagg attccgaggc aggcagatga gtgaggataa attgggttct 75900gacggcacgt tacaccagtg gactctaacg acgacctcac ctcgtgcaca gataattctg 75960ccttgtgctt aaccgttaga aatgtgtcac tgaagtgtga acatattatg ctgttagatt 76020tcccatcatt tctgttcttt cattccctct catttgcatt ggttactcat aaatgtagat 76080ctttggtatg atttgtacaa ctgccgggtg tcaatctgtg aaagaaatag cagagcaagc 76140tgggctctgg tagcgcttta tccctgcgtg ctggcttgcc cgggttgact cagaggcagt 76200ctcacattca gctgcgctgg ggccaaggac ccagggagcc aagtgtgttt ctgttttctg 76260tatttagcaa tttaagacct gcgtttaaat actagctatg cattctagca aaagaggttt 76320atattttaac acagtaactc ttaattgttt aattcagttc gtgtgttacc tctcggaata 76380aaatagtgga agccaattaa ctatagactt cattagtttg gatttaagat caccaaaaca 76440tttaccacat ctcaattgtt cattacatgc tctctctttt ttaatgcagt ttttataata 76500tggggagtgg gggtgtggat ttaaccatta tatttttatg atattgggag tagatttaac 76560cattatgtaa attggatttt ttaattttaa aaagtcactt atcttgatgt aaaatcatgt 76620cttagtaacc ttgataaact aagttttgca tgattacacc ttaaggttaa aacatatttc 76680atttcatcat ttcccagaag gggcactgaa ttcacccatt tcctgttttt catctcagaa 76740tgttctgtgt ttcctccata tctactttcc cggcagcagg accctggaag cagtcacacc 76800aacctcattt accccacctg agatttgtgc gctttgaaca tagttgcaat caaatcaaca 76860atatctttgc tcagaaatgg atatgtgaag taaaatgtgc tgccctgttc atgtatgaaa 76920tcattcagct agctggccag tgagcccttc attgcaacaa agatttttct agagcccctg 76980cactatctgg ggctatgtca ggcctcacac tcctgctcac acgtttggag gctaccttgg 77040ccagtattac cttaatccag catttagggg aaggagcatt tcaagactaa attttctaaa 77100ctgctcaagc ctacctcatt ttatttcttg tgtattttaa cacttttgga tgaggactct 77160tcctagaacc tactaacaat tcccccccgc ccccatgcca agattcttta aagactttct 77220tgaaaacgct tcagtctttt cttcttagct caaaagtact atcctaaata ctagctctgg 77280cattacaggg agttaatttg tgggcacaca cagtaaatta taaacccctt aagcagagaa 77340gattgtatta tcagtttatt agttttctta ttcattcctt cagcacacat ttctgttgcc 77400tccaatgcag cagagaaatt gacttctaca gtttccacaa cagtccagat ttcaactgtg 77460tagtgctctt tcagccagaa agtacacttg tgtttccctg gccataggtc ctgaacctca 77520cttctgaaaa gtcattgtgc atagagagct aatagctgta ccctaaatga tcctggcttt 77580gaattctctt atctgcttgg atagtattat ctgtctcttc ctctgcattc taatttgcta 77640cttctaatct gctgggaatt acaataagaa agaaccattt aatcattttt acaactgtgc 77700ctaaagagag tgtgtgtaag tgccgagaga gtgtatgagg gacttgccca tgagtaaatg 77760catgaatttt aggtcaaggg ttttttgctt ctcttttggt tgattacctc agagatcagt 77820tttactttct ttctcattct tgacctatca tcactagctg atatggatga tgtgtacaac 77880ttctgagtaa gaataatgtc aatgggacgg gatgggattg gctggtgatt ctgttgatct 77940taaagtttat atattttaag tttagtgttt cagaatgaga ccaaagcggt gacattttca 78000acctcttcgg tctctcttca gttttttcat tttaagtttt tgttgtgctt ctatcactta 78060aaggaagcct ccaagttgaa atcaaatact aatgacattt ttatctaatg tataaatgtg 78120tttttattat ttattaggaa atttatttta cttggccctc agccatgaca tatcatggca 78180taatcactat cctaaatttg tatatcttat ccttgcataa ggtaagactt tctatgaatt 78240acacatattt gtattttcct ctcttacata ttttaagaat ttttttatac tttgttttct 78300gcaaatgaaa tattgctcat aagccaggtg atggctgtcc acgcctcttt tcccctgctt 78360acccttgctt agatcttatg gtagaatctt ttcatagaag acacagaaag acatgaaaga 78420aagagctgga gaagcctgag gggctgccca gtgagtggtc tgctaggatg ctgtgccaca 78480gcccaggcac aggaggcagg gagagcaatg gggcccttcc cttccaccaa cattcagcag 78540aatttgcagc tccatgtttc caaagcttcc agggcacttg catttagaga gagagagcaa 78600gcaagctgcc tttcctcttc ctcagttctg ccagccacac tcttgccatg atgagcagtt 78660tcagccaaaa gctccttccc ctgccctaac acctcctgca aggcctgagg tctggaagcc 78720acctgcgcct gctggcccct cctttcttgt ttctgcaatg gatgttgtgg ccctgtgagg 78780gagaagagaa aaagaagttg ccctcctccc tctatcctca cctcctgcca tgctgtcacc 78840cttataagag agaagggcta accatccagg ctaatcctcc agtgatgcag gagaggacat 78900cctggccgga agagtcagag cttccaggtg agctcaggtg ggtcagcccc cgaggctgtg 78960aagagcccag gggccagtag atgccacttt tgctccagga agaatcttca actgtgtcct 79020ttttattcaa ggggctctct tttcagcgaa tctctagatg tactagtcac aaacactcgc 79080atttattaaa atgtatccat gatcccacaa tccttttaca tatttctctc caggagtatc 79140acatttctga gggccctgtg cctgttttct gcaggaagtt gctgttgtcc cgggtccccc 79200tgcccccagc acctctgtta caagaagcag acccttcatg ccacactggg acccagggag 79260gccccaagcc aggatgctgg gatcttagta aaggttggaa tgatgtcaga acatagagga 79320ggcagaattc cccccatagc atcatcctgg agggcgctga tttgtgtgct ctgccaggtt 79380catctgtgac tcaggattta aaagccccag gtgtggtgtc ccttctgtgc ctgcaaggtg 79440cgtctttagc agttctccct ggtgtggaag gatcagtggt tcttgcagcc taggcaccct 79500ccacagcaag cccaacacag gtgctgtgag cagctggttc atgaacggtg atcctgggga 79560gaagaggagg atgaaaatgg aaaaccagtg caaaggtgtg tcatccagtt ggttactgct 79620gtgggtgccc gggcttccat cccaccagag cccccactag ccagggcagc ctggcggagg 79680tgagcatcat tctgctttct ggctgcacct gtgtggacag agcccgttcc aaagcctccc 79740aggcacaggg cagacatcaa gcaaggggca gagctggggc gagggctctg ggtgcccccg 79800ttattgaaca caggcctgaa gggagcctaa gaggtggctg gcaggagata ctacaaggca 79860gaaagacagg gcagcagtct ttgtactgta cgtttttgtt ttttaagaga gaacaaaaag 79920tcaaggttga gagatgagaa atactcttgc caaaaagaga acaccaaaat cctggagtca 79980cgggtcttcc attaccctct ctagcatttc tgcttgtctt ttccctagta ttggtgaaga 80040atttttaaag taaccaaccc ataccgttgg ttacaggccc tgtggtcacc aggctgtctc 80100cccatgatgg ggatggagag tggttagtgc agaaacttag acctcccctc cagcttgttg 80160aatgccctga agtttatcta gaagggaaga tactcaagcg taggatttca gtgatgcatt 80220tggacagcat cagtactatg cttcagcgtc aaaaacgtca ctttgggtag gaacaataca 80280taatgcgtgg caatgccttt tgtgacacct gttcaggaga ttcccatagg aagcttctga 80340ggcagagtcc tcaggtgagg agggggacag gcctgggtct tgggggaagg tggagatgac 80400cagcctcatg cctctctccc cagtggcctc agtctccatc aggcaaatct tgagaagcct 80460cctccattct gcaggcaaat gactgagatg tgtgagctct gcttcccaac aggcggaaat 80520tcacatgggg aagggcacct gtgaatggcc ttctagaact atcaggaagt tctggattta 80580gtaccctgtg agagcagatg gtcctgggtg cactcggatg atcctgccta gccagctgga 80640ttgcagagtg gtcatcatta tcagtgagct attgaggggt tgagagcagt cagtgtcatg 80700tataaggatg ggttggggta ccggccaacg cccgccttga ggcctggccg ccggatggga 80760ggcgagagca caagagagtc ctggctaggt gtgccccgct ctgcagggcc acaccatcca 80820ctggaaaccc tgtgcccact gggctgcgtg ctaagaggct gtggccaatg ctcttgtcca 80880aattttactg aatctgcagt ctctcttaat tcactccaaa gtttaatgtg

ttagcttgcg 80940aataaataaa taaataaata aataaataaa taaatggaaa gaaacagtcc tcagaaagtc 81000ccagtcaaat tttaattcca acagatattc agcagtttcc tctaagaaca atgagagttc 81060tggggctagc cagtgtttct cttggaaaat aaggaagagg gaaagcggtg cattcattta 81120aaaacctgcc ctagggaggc agcgttccct gtgaactccg aggccacagt gagcagagca 81180ggctggaggc ctcccggctg tcctgcccct cctgccacat gcctgtgaaa atgctagata 81240aggacttttt ctcagcaact tccacgctcc ttcagtgggg atgtctttga ctcagagctc 81300tgccactggt tatctccacg aacagaaaat gccacagatg ggttaattca ctgtgttgtt 81360ctcattttcc ctcagtttca ggcttttctc tccttgcctg ttttcctcgc ttaaaaaatg 81420atgtgggggt ccctaaacgc atctaccccg atagatttat gttttctttt ccattagtcc 81480actttgcgtc tcagccctaa aattaagttt ttgattataa tgtaaggaag ttttaccata 81540ttttaactct ggctttttaa atacaaaaga aaaataacag aatggccttc tagaactatc 81600aggaacttct ggatctagta ccctgtgggg acagatggtc tggagccagc gcacttggat 81660gatctctctc agccatctgg accatagagt gaacttgtta ctgtccctcc aaggctgaca 81720actatgagct catactcttc tagcagttta atttagaccc aagaaaggct gtgtgtgtgt 81780gaatttgtga gagtgtgtga gtgtgtcttt gtgcctgtgt ttctgtgtgt gtctgtgtgt 81840acatgtgtgt ctgtggggtg tgtctgtgtg tgcacggctg tgtgtctgtg cgtgtgcatg 81900gctttgtctg tgtgtgtgcg cacgcactct gctaagctac tcaatgcaat tccttactct 81960tacttccctt tctgtcactt ctccataatt ctttgtattt cggttgggct ggtatctcgc 82020ggcggcttcc tcttttcctg cattcctata tttcattatt tgctcttgtt cctcttctag 82080ggcttttaca atatagccag gaggatgtgg aaacccagtt acaagatgac acacaagcac 82140agtgtcacaa tcgctgtgct tgggccctac ctcctggaga ccagggtggg acggtgtctc 82200tggatatgga gggaagggcg gaagatcacg gggtggcaga aggcccgact gtccggtctt 82260ctggaagctg gggtctcgtg gtcgctgggc tggtggtgct ctaaaaccta gagtaaccga 82320gagcaggatg actgcacccc tgactgccga ctcaccgggc ttcggagggc catgggtgtg 82380tgattccact tgtgatcctc ctacttcccc agcccaccct ggtggtctcc cacttctctc 82440tctctgcctg tggagtgtta taaccgactc cttcttctag gcatctccat cccaacccca 82500gaccagttcc cttaaaccac ctcccaccac aggaccccca caagcaggga cctctcacag 82560ttcctgttgc ctggggactt catctcagct tccaaggcct ctggaaccag gccctgcatc 82620ctgggcatga ctgtccccat gattctctga gccagccacc accccaccac ccccccaccg 82680ccaagtccac tgctgaccct gctgtagccc cccacctcca cttgttgaga ttccctcttc 82740ctgcttctca ttttgaatgt cacccttctg tgacttctca caacccccct gccacccctc 82800cctccagttg gcatggctta gtcttcctaa gaacatgtgc tgcttcccag tacccagggc 82860tgctgtgcac cgtggcacgt gagtttcggt gcatcttcct cctgctgttt ataaattgca 82920acatccctgg acagatcttg gattttccct ctataatttc tctggagact ccctcggggt 82980ttgcacacac atctgtggaa tgcccaagtt ggagatggtc ctccctgatg tgtagtgtgg 83040gctattcaga gggcctcatt tcataaactc attaacagct aggacgcgaa gacttggaga 83100agttagctca ggacacacgg agtgggaggg aggcaacgag ttaagaaatg ggctttggag 83160tgcctcgaat ttggcctcca cttttctttt ctactgtctt acctggtctt aggcaggtcg 83220ggtgaccatc tggagtcgga gtttctctca tttgtaaagc gggggtgata tttttctcac 83280agggctgctt caagggttaa caaagttaat gtctaggaag gacatagcat agcaccttca 83340cctggttgca agcccctgga gtcacatggc aacagctgtg gaaccaggta aatgacttga 83400cttacatgtt acacgctctt agttgttcga tttgtaaatg ggaagagtgt gtgacccaaa 83460ttagtcgttt ccagatattt cctggtaaat ggttgttgaa tcataaaact agaaagatgg 83520gaaagaaagg gaggaacccc ccttacttcg aagaagtgtt gttgatgtga aggacaggac 83580tttttgagac actctcatcc taagaaacag ctgatatcta ctaggaaaaa acatgacatt 83640tgaagtttct tcctaagaga tgtgaggttt tgacagaagt gccaggaagc cagaggtgtg 83700tgagtagtgg gccaatctcg cgtgaaggct gtgggacggg gcaggagagg ggcagccagc 83760atttcctgag cgccagctaa tggcggggac ctggcacctt tgctctgtga ctctccagct 83820gtatggtgac atgaggctgg cgttttcttt ggtttcatac gtgaggaagc tgaggcttgg 83880tgatgtcctg tgcatggctc ggactccaga gctactcaga ggcagaggcc gtctgtaaac 83940accttcaggt ggttggaggc agggtgctgc agccaatgct gatcactcac aagccaaggc 84000tttattgtaa gggctaaata aaataacata tgcctagcat ttatacagca cggggctttt 84060taggaaatag tgagacgacc atggagaggt ggaggaagag agaagggaaa gaagaaaaag 84120aaaaaaaaag ccttaaagag tttcttaaga gaactatata ttacaaagtc cttggagttt 84180tttttccctg gttagacata agtttacatg aaacgttaaa cggcttaaag tagccacatc 84240tccttcctta tgtcttctca cagccacttg tgagtttctt atcaagatac agaattatgg 84300ccaagtgcgg tagctcacac gtgtaatccc agcactttga gagactgagg tggaaggatc 84360atgtgtgctc aggagtttca gaccaaccta ggcaatatgg taaaaccctg tctctacaaa 84420aaaatacaaa aattagctgg gcatggtggc atattccaat agttccaggc actcgggagg 84480ctgagacagg aggattgctt gagcccaaga ggtcaagact gcagtgagct gtgatcgagc 84540cactgcacta cagcctgggc cacagagcaa gatcctgtct caaaaaataa aataaaataa 84600aataaattct gcaacaagtc acaattcctt gctcagaaat ctctacaggt gtgcttcttt 84660gttaagaaat ggaggaaaca tgaatttcat cctgacttct gagtcttgta gagaccagat 84720ctgactcctg cagccttctg cccacagagc tggcaggcgg gggaatgtgc gcagagtgag 84780gaggagctga tctgacattc cgaacagtgg agactgctgc ctatttggcc gcaccactgt 84840ccttctgcat ggaaaagtca cagtaaataa tggactctct acctgtgagt cgattttact 84900gagctgcctt tttaaatata tgtgtagaaa gggcgatctc tgtgtgtcat ttgcacatgt 84960acatacacat gtacacacgt gcacacgtgg tcactcatgt acacatgtgt gtgcaccagt 85020gcaccagacc agatgcaccc acccaattcc acgctcctca gccccttgct ttcctctgca 85080gacagccagt tcagctacag ttatgccaga ttgcctgcac tctgatcttt accatcacca 85140gactctcagc ttgagctcat gcctgagaaa tccactttct gggaggaagg cagaagaaac 85200tgccaaggca ggactgaaga cttgacctcc acctgtagtg gggtcaggtc accagaggct 85260ggctgactcc ccaggatttc tcagcagagt attacacaaa taccccttcc ttaaagatta 85320gcaaccactt aaagacacaa agtgtgcagg actgtaccca tggccgagag cggcgggatt 85380aagagggcaa ctgagttgtt cttcccatcc ctcctcctct gtgctgagtc accttctgct 85440tggaattctg acagggaccc gttgggcttc tggaagggag ggacagcaga ggatccaccc 85500tctgtgtgtc ctgggggaga ttacttatct ctggcctccc tgaagcaggg cctgggcttc 85560tggaatcttt gaggctgaca ccctgccagc cctggggatg agagggaatg gccgtgtctg 85620tctgcagagc ctgaggagga gctgagcaca gcctccagag ttctcttcag ttgatcgctt 85680aggtggacaa aggccacaga aatggattta aactcctcag ccctttcttt gcatgtttgt 85740tctcatttga agtcagaagt gatatgtcct acacctcaag aacgtgtgaa atgcacatac 85800aataacccca tttcaggaag ccaagtccag cttaacagtc aaaacatttc cttcagtctt 85860tagtccttca ctttgccgaa ctccctttta caccggcagc aacagtttaa cctgttgctt 85920ctgtaagagt gtgctactgg gaaaaccaca tctaaaacac gtgtgcagtt acatcagcta 85980gagcacatgc taaacagttg atcaaaggct cttgccttgt ggcccacgct gcagacactc 86040tgacgactgc cgagctccgc agccccatgt cgtcccttcc gcactgcctg ctgtgcctct 86100cctctccatg tggcagggaa cacagccagt catcaccatg tggctctgcc cggcgctgcc 86160ccagcatgtc ctgacagggc ctagatatgg aaaggtggct ctccatgcac acaccccaag 86220cccctcctgc ccgccgtgtg acccacactc ttatgggcag cccagttatt ttgtagcatt 86280tcccttcctt atcattttgg cccagtgatc cagcacaaat ctcccttatt agaataaaat 86340ttggaatgac aaaattaaat ttcatttttc acttatattg aggacctcac actcttcacc 86400cctgccacga tccctgacaa gagccttcct atctaatcat tgttcctcca gccctcttag 86460ttttcttcag cctttcttga ttgcctgaat gtccctttcc cttctccttt taaagcatga 86520accaagcttt cttaccccgt tctcattatc atttttgcat tttcttcttt gcatatgatt 86580ctccttaaat tataaaactt gggggtaatt tctagaggtg ccatcatagt gcttctgtct 86640actcagtgtc tttagaatca gcaaatatca tttttacaaa aaagtagtat ttcttccaaa 86700aaagagtaag caagaaggtt acaacactgg gaaaatatcc ctaagcctgt tcttcaacct 86760gttgaatgtt ttcccctaaa ttgttatatg gagatcctgg acccggaagt tggctgacat 86820gaaacaggcc tagcagggca gctgaggaaa tgctccaacc tcaggatcca ggaagattgc 86880acatggcacc aaaacaatca tttaaaagct aatcctggcc aggcacagtg gctcacgcct 86940gtaatcccag cactttggga ggccgaggtg ggctgatcac aaggtcaaga gatcgagacc 87000atcctgacca acatggtgaa accccatctc taccaaaagt acaaatatta gctgggcatg 87060gtggtgcgcg cctgtagtcc cagctacccg ggaggctgag gcaggagaat cacttgaacc 87120cgggaggagg aggttgcagt gagccaagat catgccactg cactccagcc tggtgacaga 87180gcaagactcc atctcaaaaa agaaaaaaaa agctaatccc ataaaagaac catcattttg 87240aacctgctgt ttcctttctt gtactcttta gaagtaccca tttctccctt tctaagccat 87300aggtgtatta attggagctt tttctatctt aattagttca ctgtgaacaa ttaaaattgt 87360gttaataaaa caaaaacaaa aataggactg gtgcctagtt gtactacatg aagagagaaa 87420gggccagaca ttggtttttc ctaatcttct gtcaagttct ccaaatcatc tgctctggaa 87480ggtagctcca acagctggga tttgaagtaa agcatagtga ctttggccat cactgacatg 87540tcccatttga agcaaccaaa actgtccctc gacctgacac tcatccctga aacaccatga 87600gggtaagtga ggcgcttcgg aaggtccact caaccccatt gccagataga gtaagtgtct 87660gccaggggca tttggagctg aagggaagac tgtacagact cacggtttgc aggcactgaa 87720ggcgttttcc tgccttcttt ttcaccttca gtggacttgc aaagcactag ccctattgtt 87780tttcccatct gggaaacatg gtgaatgttg gttggttgta gctaatccta tgggtcttga 87840ggtctttgtt gacaagaagg tagatgttat ctttatctgc gtgtggcttt ctactaaaac 87900atgagctaca gggctctctt ttttgtttta aagcattttt ccataaggtt cacccttact 87960attgcttatc tgaataatat tacctgctga gaagtttatt cattgctcac cagttgtagg 88020gagattttga cacaggactg gaggattttt ttctcatcgt aacagtgcag acccatggaa 88080agcttggaag cagttgtgac cggataagag caggttgagg atgataatct tagggcaatg 88140agcaggttga ttgagagggg tgcctgaaag caaggtcccc atgatgcaag caaacaaact 88200cacatgccag acggtggaca ggaaacacag gcaggatgtg gtgcaggctg ggctgccttg 88260gctgggcaaa ggcaggggct tcatggccat gctgggatgt gacgtggttg gaaaacaata 88320agaatggaga cctctccaaa gacctcagac ataatttggc catgagaggc aagggtagag 88380gcgagccccc tgtgggttgg aatgtatgga atccagatga agcaccatca acatgcatgg 88440gctacatagg agagctgggt ctgggggaaa agatgggatt tgggtttggg tgtgcatgtt 88500ccaggcatgg agggaagaat gggcagaatg acgaggatca agccctggtg gagcccccag 88560accagggccc tgggcatatt tccacttgcc ttcttctgca aacttttgtg tgcctgttgg 88620gtggaaggta ctatgctggg gccatccagg atccggagca gtgtaagaca tcatggcctg 88680catggtgtga cccttgacat ctgaaaagaa cgagctggtg gagtgggaag gagacaagtg 88740gcagcagagt tgacatcatc aggactgact gcaggacagg cggtgaaacg agccactgag 88800gagttaccca gtgccctggg gagcttagat gtgagactta caccacccag cactccccag 88860ctctgtgtcc ctgggtccca ctgaacttga ttgtatttta gttgcctctt ttctaagacc 88920ggagcaacaa taccttcctt gagtgtgcat gtgcagtcca tagatggcag ccagtgttct 88980cttcccatga gaagactctg agcctcctca ctagagggtg gtctaaaaac aaatggatcc 89040atccacagaa ggtctgaaag gttttcatag aatcttgact tggtagcact tcaggatcta 89100actcgtgctt tccagaagtg tggcctgtgg tgttctgtct ggagtatttg gtcctcccat 89160ccacctccac cttgctgtcc tgtcctgtga ctctcactag ctcagtcacc gggtcaggaa 89220gccctgccat gaaatgctag atttggaggc attgccaagg taccacaaac catactcaaa 89280caaggtcata atagactagt gatctcactg tggctaacag gttcatgtga tttaaagaat 89340gacagcattt tttctaaatt ttataaattt tataaatttc tcctaaatac aaatctgaat 89400gtgtttacct ttagacagat tttcccagaa aattgtcagt gttctcgaat ttgaaagtag 89460atcagatctc ctccctctag ttttgaaaat ctcaagtagg tttagcctct ccccagagtg 89520acaacggcac aagaagttta taattttatg cacagctaaa tgcaaactga aaagtgtggt 89580ttgtgggtat ttcatttttc ccataatgtt catcaatttg gcaattcaaa taggattcag 89640aatccaaggt gttcgcagca ttttatatga aaatgtgcct gagagtttgg ggaatagaaa 89700ttcttaccaa ataagttaaa tttgctcttg ataagaatat attttgtaaa atgtagaaaa 89760ctgagaaaaa aagtttgaca cctgttttat ctgcatcctt ttattaaaca gtggcctgaa 89820tttactaaag gacagagaac agggttgaga ggtaatcact gaataatagc ttcgctaatc 89880ccacagtgac tgcttcttat gacaagcaag agggtcaact tagaggcagg actgtcttca 89940ggggcaaaag caagtcagca cctacaaacc tctccaagag agtgagaaaa agcaggttgt 90000atggctcatt ttgcagcttg ccagaagcaa tgtgggaata ttgtcagact gcacagacct 90060ggggccagct ggctcctaga gtgcgaggag ctctcagtga ctgctgtgca tactcacctg 90120ctctgtgact ttgttcagtc cctaccctgg atgtgtggtg aagggtgcca ggcttagctg 90180ctggaccagt gaggtccctg agggggcagg gctaagaggt gtagcagtcg cacttgacca 90240gtcattgatt cactggttgg gaatttgttc attgagggga caccattact ccccatgcct 90300cacgtgcagg tgagtgtgtg tatatttgca ttaacacaca aacacactta tgtgtgtccc 90360tgtatgtgca gctgcagtac cttacacatc ttccagtgcc tctcaagcat cataaaaaca 90420gcttccacaa aacctctact acccacctgg catccacaga gctcccagtg attggctccc 90480aaaagatact gaactttggc atggaacaga gtgagtttcc acatttgctg ttgtacataa 90540ttacctgtcc agctagaata gtacacactt cttttactga gcccagaagt ttatgtgcct 90600gaacacggat ggtacaggaa caagggtgag cgcttatcaa ttcagcatta ctctggagac 90660atgaaacaaa ctaataggta cagctatatt ttgtttttta aacaattttg tgaaccacat 90720atttgggaca aaaatcaaca agtaaatttg aattacacta ggcaaaggac tgattctttt 90780gaaacgtgat tgacattcaa cgtctaactt tccaaaagaa gacatacatg tggcccacaa 90840tcatatgaaa taaagttcat catcattgat cattagagaa atgcaaatca aaaccacaat 90900gagataccat ctcacaccag tcagaatggt tattaataaa aagtcaaaga atgacagttg 90960ctggtgaggt tgtagagaaa aaggaacgct tatacactgt tgaggggatt gtaaattagt 91020tcaaccatgt ggaagacagt gtggcaattc ctcaaagacc tatataccat ttgacccagc 91080aatcccatta ctgcatatat acccaaagga atatgagtca ttctaccgta agacacatgc 91140acgcatttgt ttgttgcagc actattcacg atagcaaaaa catggaatca acctacatgc 91200ccatcaatga tagactggat aaagaaaatg tggtacatat accccatgga atactatgca 91260gccataagaa aaagaatgag atcatgccct ttgcaggaac atggatggag ctggaggcca 91320ttatccttag caaactaacc caggaacaga aaaccaagtg cagatgttct cacttttaag 91380tgtgagctga atgaggagaa tacatgggca catagagggg cctatcagag ggtggagggt 91440gggagaagga agagtatcag aaaaaataac aggtagtaga tttaataccg gatgacaaaa 91500caatctgtat aacaaacccc catgacatga gtttacctat ataacaaacc cgcacatgta 91560ctcctgaact taaaagttaa attaaaaaaa aattaatgtc taataatata ttacagtatt 91620cttcatattc aatggcaatg tgtgaagtgg gaagtgtctt gacagaattc ggtgtttcaa 91680ggcttacact ttgatgccca agactgcaca aggctacatt ttctactggt gagacaaatt 91740ccagacgcat tgcattcaga tctaatctct tagctcctta atcttcaggg tactggtaaa 91800catgaagacc tccccagtgc tgtagtcatc atgatatgta cagcaggtgg ctgagctctg 91860gatgtagact gcagggatat attaggaagt taattctcaa ggcaagtcat cttcaagcac 91920catatcagca tgatcagcaa tataagtagt atctcagtgc tttgttgttt agtcagagtt 91980ttgtactcta tcacccattg taatgttcct atttgcaaaa ggtaatacat accctttaaa 92040acatctttgc tttttctccc attatcgaga tgctagcagc ttcataaagc agaataacta 92100agggcaaaca gattatataa agggttggag ctcaatgaag acaacaagaa cagcaaaggt 92160tattgtaaaa ctggctgctt gcaggccaac aagcacatcc atatggaggc aatcagttta 92220tgctacctct gtctgtttga tgggattcat aatattgact ttatccatta gatttggact 92280accagggaat aaaataagca gatggagagt aaggatttgc taggaaataa ttcagccagt 92340cactttgaaa gctgttcaag aaacagcttt caaagtgtct ctcaaactat gtttgcccat 92400tatcccaata atttatttcc caataatttc atgggaaaag aaggaagttc tgtggtcaga 92460taaatctgga aaacactggt ttaagcaaag ttcagtaggt ctgcttccct gcaggtcacc 92520tcagagtctt tactctgcta acctaggaac tcatccaaca agtttaattt aacagctaca 92580ctgtgtacgt cactttaaca gtcactgagc tgtgactctt gggggaaaga ttgtgcgtgt 92640gtgtgtgtgt gtgtacacat gtgtgcacat gtgcagaatc taccaaatct taagagaaag 92700gaacatgctg ggaaactgtc ctgtgaaaga gaatagaaac ctgaagattt gaggcagtga 92760tagcatttat gaaagcagca gataaggact aatcaccaaa aggggtagct cttttgttgg 92820ttggggaaaa caggaatttt tcccccaccc aatgtgctgc attttctaat tttctatgaa 92880cacttcctaa gaaaaagctg aatgaagaac atttgcgatg caatcagctc attaagaaac 92940acgcactttt gtggagatac gtgctgtccc aggagatgct ctgcgaggag ccgagtgttt 93000ggactggagc tgctgaatgg tttctcacag ttctagaatg tttggggctg caccctctaa 93060gatgttgaac ccatcagtaa ttgctccaaa ccactttatg ggatataatg ctgtgagttg 93120acacctgagg ggattgtggt cctgttcatg agtaattact tttctgttgc ctatagaagg 93180gccagcaata gcagatgagt agctgaacag tggttttgag taataaaacg ttctttttta 93240aaaaaaagta atgctttctg ttaaactctg actatactct ctcctggtat cacaacccag 93300ctttcttttt gccttcttta ttgcagttac atatggggct gatgacttta gggatttcca 93360tgcaataatt cccaaatctt tctctcgtaa gtatatgcct tgcttctgga aaacaaaagc 93420atgccttcat ctcctatcat gtaaatatcg tacgtgcatg ttccttcatc aacccccgag 93480atacattaaa tattcactgt tctattcgtt agacacctac catatcattt ttgggtattt 93540ataccataaa gtgcaaaacg aaggtctagg cagttgtgcg gtgtcctggg agcatggcag 93600tggagtaaca gtaagggttg gagtcacagt agcactgatg ggattgttac ttcgcagatg 93660ctgctggaca gctttgagat tactcctgta atccttttta ttgagtgtga ggataaaatg 93720gccatatttt ctgtcaccaa caaagaactg aacatggttt caagataatt tttacaattt 93780tgtgggacag gagaaggaga tatgctcttc atctgtggtt ctggagtatt aatttcagaa 93840ctgagaagag aaaattgcag gcctccaggc cgttattctg tggtgcatcg ctgctggagc 93900caacgtactg ttcctgcttg gtgcccgcag gaccttctct gatctgagct gttaaaccaa 93960aaacagatgt gaatttcatt tttctttttt agatattgag ctgataaatg ataaatatat 94020ttgggtaaca tcctcaaatg agtactttaa agaacagaga gtgcttttga aaatgtatag 94080agagctgaat atttaaagcc atacaagttg ataatcccct taggacctgt attagtaaat 94140cctctaatac tataaagcaa catcagaaaa caggtcgcat ttgttaacac tgtgacaatt 94200ataattatag gctctaattt gaacagtgcc agtaacagtt aaagacaggt gtctgacatc 94260ctggttatca aaaactatct ggtgtctaag gaatttaaca gtatcaaagt acatcttttt 94320gctcacaaac tagattggct acttttccag cctatagaag ttacagaaat ctttctttta 94380ctgatattcc tttgattcca ctttaaagca atagcttgat acctactttt tgagatgtat 94440atgtatgtac ttgtaaatgc ttatatatgt gtatttgttt acacgtgagc ttatatgaac 94500atataaaaca ttatggtatt ggacagagaa atgatattga tttgaagaat catattgttg 94560aagtattttg agaagtcaaa tgcacttgag agtaagctaa tgcatcctaa aacatgtttc 94620tgtgaagtct gaggaaggtg tcagccagag catatgttga agcagaccct tcagtgaagc 94680cttcagtctg taagaatcgc tgcatgtgaa gatgtgttaa tgttatgata gttacagttt 94740ttataaaaga gatgatatac acttggatat gctttctgtc tatatttatg caaatgtgtc 94800cataaggtat tggtgtctct ctttctctcc cactctcccc agtgttggaa ttgtgactat 94860cttctcacac aagcggctac ttggtcttga tgccttcccc cgcaaaacag caaccaaact 94920gttctgggcc aatatcacca ccttgtggtc atgatgaaga attgccccct ttgccctcaa 94980cacctctttt cttcttgaaa attaaaaaca acccctttca ccccctctac tgtccttatt 95040ccagtttgtg tccgtagttg ctggaggaaa gaaaatgcct attgctcttt tttttattct 95100ctttatctgt ttactcttct gcctttcttt tctctccctg acttcattcc atttaaaggc 95160cttaaattgc aaataacgaa aaaagtattt tctaataata taccctagtg ggacgaaaac 95220aaccttctac attttaaatg atattaagtt ataataaatg gttccatgaa ctttaaaacg 95280cttaaaagtt ttataaatct cttttagagg caacacaaaa atatctatat atatatcttc 95340tcttcacctc aaattttcat ttaattaccg tgattcaaga tatatcttaa atatttccat 95400ttcatttgat ttttacttgc tagtcaccag tgttgcaaga atatttctgt accatttttc 95460aagtaaaata ttgagcattt caagcttaca tggcctaaac tcacactaga gtgactactt 95520cggactatct tttcaatgga aaaatgcgtt ctgagtacca aacatttact ttttcagtaa 95580atatgaagac acattctaaa aaggaaaggg aaatgaagag gaagcttaat tcattggtca 95640ggtggggact aacagtgtac attataccta tgcattaaaa aatgtttaat tatccatgag 95700cacatacagt gcctggcaca gattcaggcc tcttggctcc tcttggcatc tgagttcctt 95760ggattctcca gattcttcaa tccaaacttg tctatctacc aaagtccacc ttccatacag 95820gggtgtgggg tctctcttag tactgttggg tgccaataac atagaagccc tccaagatag 95880gtcaatgaga ttttaatttt tcccaacttt aaatagcatc tgggaaggaa agcagctttt 95940gactaggagt ttgaaaacat ccactcttca tatttattgt cacatttatt

gagtaataaa 96000attgggctct tgtccattat ctctcagtca atgaaagagc ccacggtggg catgagccag 96060agtgttccgg agaaagagag gaccagtctc catttcatgt tctatattta atcagttcaa 96120ttcagcacct tactgagttt gacatttttc taagtaatgg ggtggggggt tacaaaatat 96180ttataactat ctttcctatc ttcagggaga tgtaccattt cactgaagca ataccacagc 96240taagcagttc cagctccgag taacagagga aggagtgagc gatttaggaa ctcacagaag 96300ggcacggcca ggcaactcgg gccctggcaa atgttccata gagacagcat ccatggggtt 96360gaaccaagca caatgcctgc aaatcgggca ggcgggttca tggaattgat tctagggcag 96420gtatgatcag caccatttaa ggagtggcag ttgttaagaa actgaaggga tttctcatat 96480ggcattttca acagaattca gcaggagcct tgcatatccc ttgggatggg ttccggggta 96540ttatggagct gccaggaggt gctcagcttc agtaagtgcc agtcattcct tcccaacctc 96600ctccttcatt agtggaagta tcagctggtg tcattgcctt cttcaggagg atggatttca 96660aaatgaaggg ccaacaaaac tcacattctc gcagagcctc cgtcacaact gcatgtgttc 96720actgccatca acaggccaac acccacttgt tcttttcttc taggtaaagg aaaaggtctg 96780tgggacaaag gccctgaact cctcactcct tgaatgggag gcatattggt ggaggctgtc 96840acacaactac aggtggcagg aacctgccat cagggttccc atcagcctcc agggcttgct 96900tctctgccct gtgtgtggac accttccatc actggaaacc cctctctcag aagaaccact 96960tcttgccctc atctcccact tgcctctcct cggcaccttc tccaccctca ggggccaagc 97020tgaggaagtg tgcatcctgt gccaccaacc ttgctcgcag gaattagttt cagtccccag 97080tgactgactc ttccaaacct gcaccagcct atgctgccct tttgaaagga ggcgtgcgta 97140cagcctggct ggtacagaag attccagatt tcagtgacta caggacgctg tcaccccttc 97200tgtttttctt ttttctgtcc acatctctga ttgagcatac cttcagggaa aaccccagaa 97260acctttttca cacttacatg ggaagccaag acactctcat cctgggcttg tgtttttaaa 97320atctatattt taatttcaca ggtccttaca tttatgacta atagatttca gattttgaga 97380tacaatctgt agttgcaact tatgaagata gtttcaagcc ctgatttctg tcatctatga 97440aaacagtaag caagttgctt gtattctcct cctagctgga taagagaccc ccgttttcat 97500ggacagcctc cttgggtgga cagaagtctc ctgatcttgt ctatgtaacc agcacccact 97560ttgcattttt ccgcaaagaa aagaggagct taaccccatt tacgggaaat ccacgcactg 97620cttgaatctt acgcgccccg tggtgacggt gttgcccact ctgttccctt cccaccaaat 97680cctgccagca cctggcagtc atccagtcct tgtcttagac ttcaccaacc tttcccgtca 97740taacatggct tagaagttgt ccgaatagtg ctagaagctt tcagccctgg aatgctcagc 97800atctgccatc taacttccat ttaaaacgtt ttgagcattt gctgatacag gttcctctgt 97860cctttcccca ttattttcag ttccttggcc ttgcccatag tgatctgtgg atattgtctg 97920catactcttt tttagaaacc tagagcatcg cagtgtcctt aattttcctc ttcaaactct 97980atatattcct gagctgatca tccctactgc tgttcctaca gaactgtgtg actaatcttc 98040tatatatgtc cctacatcta gccatctagg tggagatcta ggtacctatc tccctaaaat 98100tgtacttggt atccacattg acctcaggac agtatgtgat aggctcttgt gccttttcga 98160ctaggagttt gaaaacatcc actcttcata tttattgtca catttgttga ataataaaat 98220tgggctcttg tccattatgt ctcagtcagt gaaagagccc agggtgggcc tgagccagag 98280tgtttgtgtc cctagttctc ttttggttct gttacagctc tcagtgacag tgtcattgag 98340gctaacaagg acagagtact gctttcagcc accatttgtc caatgagtgg ctgatctcca 98400ggcctctggc tttgagaaca tctgtgatat ctaaggcagc atccattgtg ggctttcccc 98460catgcttctg tttccttcct gtcacatagc tttgcctcct cctgcaagca gcctgctgta 98520gcagaaccgg tgttcctgaa gccagaaacc caaaggtcgt gtccaatgct tccctgctgt 98580tctgctcccc acctgcaagc gcccacacac tgatcaacag cacacgccat agagcatgcc 98640aaagaatccc agaaatactc attcttaatg atccagaaga acaagtgata gcttctggca 98700agttctaata ggccatatgt gcccatggga aagcaagagt caattctctc tagctggttg 98760cctctgaatt tatgaagtca agccgcgtag gggaacatgc caagaggatt atcccaatgc 98820ctgttctgcg tggtgtcctt tttctagcct cggaagcact aggcctacac cttcgctata 98880gccctcgtct tagcgcctgt atttgaaaaa cttgccacac caatcttaat ttgctccatt 98940gtgttctaat ctcattttaa aaaccacaag gtaaatgatt aaaaataatc ttagattaag 99000gagtacacag atctttgcag cctcattgtg tttccagagc gggctagtgt agacactggt 99060gaacaaggag ggcctagaga attagctttc tcccagaaag atgcacagcc tctacctgag 99120agtaccaatt ccagagaact caatggtcat taagcaccat tgcctcgaca gccagccagc 99180ctcacttgcc tgcctatctc ctttattttc caagtatctt gtccctggca gtggggagag 99240gttagcagga ggctgctcag atgctctcgg tctctgatct tcaggatctg aaggggagag 99300catttgaaga atccccattg ctggatttct caggacaatc ctgcataatg ccaggatctg 99360atggaggaga caggcagctc tgttaatcct ctggtgcatc ctcacttctg tggtctccaa 99420gtccaccatg tcccagttaa ttcatttcat tattcatctg taagtcattt ccctaaagag 99480ctaataagaa aacactggca gtacaatcag ccctccatat ccatgggttc agcctctgga 99540aattcaaccc actgtggctt gaaaatacag tattcaagag acatggaacc tgtggatata 99600gaaggcagat ttttcgtatc cataggttct atagggccat tttagggact tgcacatcta 99660cagaccttca ggagtctcag aactgatgca ctgcagatac caagagatga ctgtaagtgg 99720ttaggaattt ggatgctggg gccaggctgc ctgcagttac cttccagctc tgccacttgc 99780cagctatgtg accttagcaa gttgttcaac ctctctgtgc cttggcttct tcaactgtaa 99840aataggataa tgatagcact tcccttatgg agtccttgtg aaggttaaat ggcagagtac 99900aattaatgtg ctgtgtgccc agcgtgtggt attggggtta ggtgaaagac tgtactggga 99960tcactggggg tgagcctcca tgtgccatgc cccaaccact atcctcagct aacttcttgt 100020ctgtcagtgt taggctggtg ctataataat ttccattttc atggatgagg aaatcaaggc 100080acagagaagt tacatgactt gcctaagatc tcagtgcttt taaatagtgc agctaagatt 100140ccagaccagg tatttttatt tcagtgtctg gactgtagat ctctaaatcg agaggaactc 100200cctgaataaa ataagcttgg agtgctgtta actaagttgg ttatttaaga cagttgttct 100260cagtcctcag tgtacattag aatcttctgg agggtatgtt aaaacagact gctgggccca 100320ccgagagttc ctgagcctgc aactctgggt tgagcctgag agtctgtgct tctagtaagt 100380tctcaggtga tgcttatgct gcttctccca aattttgaga accattgatt gaaaatgttg 100440atcaaaaatt atgtggtcta ggctgagcac agtggctcac aactgtaatc tcaacacttt 100500gggaggccaa gtcaggtgga tcactgagct caggagttcg agagcagcct ggtcaacatg 100560acaagaccca tctctacaaa aaacaccaaa aaaaaatggc tggatgtggt ggtgcacacc 100620tgtagtcaca actactgggg aggctgaggt gggaggatca cttgagcccg ggagacagag 100680caagaccctg tctcaaaaaa gaaacattta gtcttgattg tcatctatct cattgatcat 100740tttacttggc aaaatttacc tacttactct tattagtctg taaaaatggt tattaaaatg 100800gtggctttca gtgtaactac aaattctctt agtcattata gtgttggatt caccaatgta 100860tcatcagtca gtgtttctga agtgtgtaaa tgaaataact cctactttct ttaggaagaa 100920aaatattcaa atgacataat taccttgtga tgtgtgactt aaaggtaaca gtaatgcaga 100980gtcaatagtg gtcattgtat tcaagacact aaaagttcac ctcccacccc ccccccccac 101040ccaccaccca acaaacacac aagcttcttt ccctttggaa aaaaaagctc ttccagatac 101100ctacattcat aaactatccc aattaaccct tcagcaagtg gaagaagtgt aagaaaggat 101160acctcttctt tagaacacag ggtttgtttt tatgttattt aagataaaca ggaattcaaa 101220tggtcatgta ccaaagcaac acaaagaact tccggaaatc tgaaagggaa ctgtggtcag 101280aactctgagc atttttatgt ttactgagtt ttgtcccaaa gtttattaat gtttacatgc 101340cacaaggaaa ggtagcatca caataagaga cgtttttcag gcttgataac cacttattag 101400gtattttgcc aaacaagttc acacatccta gagagctgga ttgtgtgacc cagaacccac 101460cctctagggc aaggtgccca tctgatgggt agggtgtagg agtaggcctc agaccactcc 101520tgacgtgaac ctgcttaaag tgagggccca attctaaagt gggaactatg taaatacctt 101580tctagtgcat tttcagataa tcgccactgg gcctatggat ggagagggct ggcagatctc 101640cctgtaaccc caggtgcatc ccgaggcctg ccaccgaagc ccactcaagg ctgaatgcac 101700ggcgagctca ggctgctctc cccttggtat ttgctaagaa cttctgttta gtagctctcc 101760acacctattt gattgtcttt ttgctgctgt gttgttttgt tgagtttttt ttttgcaatg 101820acactgagtg gcctcctgta ttgtttcttt cagccagtaa tgttaaagta gagactcaga 101880gtgatgaaga gaatgggcgt gcctgtgaaa tgaatgggga agaatgtgcg gaggatttac 101940gaatgcttga tgcctcggga gagaaaatga atggctccca cagggaccaa ggcagctcgg 102000ctttgtcggg agttggaggc attcgacttc ctaacggaaa actaaagtgt gatatctgtg 102060ggatcatttg catcgggccc aatgtgctca tggttcacaa aagaagccac actggtaagg 102120cctggctcag tttttccttt agtggcctgg agaaggtgca tggggtttga aggaggaaag 102180catcctgtct tccttgtgtt ctgagcatgt ttctaattga ctggtagctc agttgttgca 102240agcgattggt tccaagtggt accgagtcat agagtccttg ttctggtaca gccttgtaaa 102300ggacttctca acacgtacca attccaccct ataaataaaa caagggaaaa gtgaacagca 102360tcacatgaga ggcttggcga gggctgctat tatagtaaca catactaagt agtctcagct 102420gagccctcag ggtacgtgtg ctgagtggtc accctccaca aaacaaaaaa tcctgataca 102480ccaaaactta ctcctcaaag tttccactga gaaaccatga gtaaaatgtg tgtttaaatt 102540gtatccaaac taacagggtt tgatgtttag aaacaataat caatgatgga atagcagcaa 102600aatcgagttt tcagaaagac ctcagatgag ctttcaaatg gcttgccctc taacaggaaa 102660gactttgaat cagatgcttc tattgccact ggttatcagc tcaaattcct aaagaacttc 102720atcccaaata ccctgtcttg ctgaaaggtt tactggaagt ataagagaat gtcatgttct 102780gtgtccagaa aggaaggaac acgggcaccc tagtgtcagc gagttgtgct caggctcaca 102840ggatgccccc tcaccagagg cgtgggaaca cggcgagccc cagctggccg cgctctgcca 102900ctgtttctaa tagccggtca cgttgatgga agtgtcacag agttgtccaa cagaactgtc 102960cagtcagaaa accaccactc atggtgctgg agtgtcttag aagtaaaata tgaataacac 103020acacttattt aactataggc aggaggtttc ttatgaattg aagagaaact tttctttgcg 103080tgggaagctg ttctaaagtt gggtaaaaca caatagatcc accacctcta gcagccactg 103140atagctgaaa cgtgaaacat agagacccta agctatcact gcctctgagc tggcattgtt 103200aggtcatcat aaagctagcg tctcccactg caaaacccaa gaggaaaaaa atagttgaaa 103260atcctatttt aaaggcctag cagattctat aagatacctt gggaaaatga tgacgatgac 103320ttgaaatcag accctcgtat gctgcttccg tgggggcgaa caaaaatatg ttcatcaaaa 103380attaagcaga aatgcagaaa attttgtgag ccaaaaaagc tgtgttatca ggaaatgcag 103440atatttgtgg ggttgtaatt ttttatattt gaatcgggcg gttttcaaaa tgatctattc 103500catttgtagt gtatctgaaa acctataaaa ataagttgat atcaatagat atccatcttc 103560cataaaaatt caacttctaa aattaagcaa actttgcttt ttctaatggc ccctttatcc 103620tcaaattacc cactgaaata gacggatcac actcagccct aagtgaagca agcgtgcatg 103680agagtagtcc cagcctcgcc tttgtaatga ggtggaaatt aacatgaagg taggctaccc 103740tgtgatagac acttaacagg atactcgggg acccatggta atacatccct gataaggaat 103800agacctcaca aatgaactac ttgcctgtta attcatttaa agcctgactg tacagtgaaa 103860attctcttaa ataaatattt gataagtgaa tcaaattctg gcttactaaa ttgccaaaat 103920ataatgactg cctgccttga taaaaagaat aattacattt aatgaataaa cctgccaagt 103980acagatatgc caggtggcac ctgctgtttg ctgctcactt ctcccaacaa atagcagcta 104040ggtgccacct gcacaccaat aagctgagtt tttcacttac ggaacaaata actttcagaa 104100gtcaatttta tagtttctgc cttgcccttt gttaaaaaaa tacacacact tgaagcaatg 104160aactcatgaa ttgttttcat catgcatttc cacttgccta aatataaagg gtcccaggta 104220gatacagaaa tacctggttt ggccaaactt ggtttgaata actagacatg ctagaaaagg 104280ttttcatttt cctgggatct gagtggaata tgttagaaaa ggcatgcttt ctgaattctc 104340tatgcttaaa acatttctag agcagtgctt ctcaaacttg aaagagcatg taaatcacct 104400gagatctcgt gaacatacaa ctctgcttca gacctggggg gaggcaggag agcaagcatt 104460cctaacaagc tcccagcttg tggagcacag agccgcctca ggcagcaggg cagtgcagct 104520gagcagtgac agtgaacagg gccattcaga gggctctcca cctggggctt aggtacgacg 104580ggaatcccca ctggacaggc taggacttgc actgtggcca ttgttcctcc tcctgcccat 104640ggctgagtca gcttctcagt cccttccagg atacactgag aggattcagg ggcggtctcg 104700cctctgccca tatccccacg ttggtgaagt accactggcg ccattttcta atcagctcat 104760cggcaccagc acgtcacttc ccctgttgtg cagctcagtt ttatatttct gactcgggtg 104820taatagtaac atcttcccca ccaatgtctc agggttattg tgagaaccag agaggagaga 104880ggtaggaagg aagcaggaaa tgcagggtgc aaatacacca cattattatt ctaaataatg 104940ggatttttaa taacaaagac caagaagatt gtctgtgcct atctagttcc catctgtaag 105000ataaaaaggt gcagtccctg agcctcctaa aaacagcacc ctaatggcac tgctcctccc 105060aggtatgatt gcagtagacc tacgtcagtt cttgcagttc aaacacattt tttcactttc 105120ttctgaaatg ccctcaaatt ctatgacata gtatccatga agacttccct ttttacccag 105180tgaagttact agagggggtt caaaccttct tacagagggt tcctaaaatg ggagatctgt 105240ggagtcattg ggattaaaaa ttaaatttca aattcatgac atcaatgtcc tcatcccagt 105300taaataaaag taaatacaac cttgaagaaa tttgacctac tcagctgcaa tagctgttga 105360cctgcagaag gcaaatgatg gaccccggcc acgcaagaac acacatggcg tgggctgcgt 105420tcttgtgccc cagctccatg gacgtgtctt cttagctgtg gacccctcca aaggaaactg 105480cttgagtgga gtgctctgta ttgtcactcc tgggaatgct ctcttaacac ccccatgcct 105540tgtgctatgt gttcatacca gcataggcac tcagaagcaa aaaaggtttc cagtgaaatt 105600tgtttgcagg caggtattaa gacatcagac actgcaggat ccaagtgaac ccctgcccgc 105660ctgcctgcct gccctgctct gctctgcaga agggcatgtg tctgtagcaa tctgcccttt 105720ctgtctgcga tgggcagaga ccctggctct gcctcctgtt ttccctgtag ccctccagac 105780ctggggagag acatgggact ccagcacctg cccagcacgg aagggggtct ttcccaggtg 105840taagtgtagg gctgcattca ctaatttagg gtcataccac aaacactgtt gtgtcaccag 105900gatgttgtca catgcttatt gtgagcattt ttgtgacatg agctttctcc tgagaggcca 105960ccctgtccaa atgagagctg tagttggagg cacatccgtc tcatgctgcc tgggtctccc 106020tgcaccagct cactctactt ttccttttta tccacttgga gttaaatgca cacatttatg 106080cacaagtgca cagaaggccc agaactgttc ctaatagata attaaatgat ctctctccag 106140tggaaactct cctgggctac ctggctgcta gctgttttag cctcttcatc cagtattgat 106200ttacatgcat cggtttgtaa ctcagacagt atagttagtt agtttgtttc accatcacct 106260tccaacctgc ttacgtttaa actccttctc tctgcttagc taatacagat ttctgtaagg 106320atttggagaa ataccagata cctcctggtt agtatcagga cctctccatt ggcctataat 106380tgaacatcac tgtaaattag tttcagcttt tatagtaatg catctaaccc gccagcttaa 106440aaaaaaagtg atgataatca tgaaattcaa gtgtcaatat agacttttaa atctggtgtg 106500gatgttaata gtgccagata tgcttctgtg taatcatttt tgagaagtgc tgtcttcttt 106560accataatca cattaatcaa tcgggaaatg gttaaataga cattttaata cattgttttt 106620tcctgagaaa aaaagtgact ccaggaaata tgttgttaca atatctcaac accaggaatt 106680gtggtcacat agcattcttc ttctaaataa agcatttgtt ttacaaaaga gtttcatgtt 106740tacttaaacg tgacaaatgt atcactcttc gaagtgagag ttaaatgaaa tgttccctga 106800tttagattcc aagacctgtg actactcagt aggacaatag catatttctt ttactcagat 106860acctgtttat ccctttgtca gctccagaat ggagacacag gtgctgccac acagaggaga 106920gggtcaggtg ttttcttagt cacaaatgca gcagtctcac ccctgaaaga attccttcat 106980aacaactaaa ttgcacctct tagaatacct gtacttaaaa tataatttgt cttctatgga 107040tatagacaaa taatagctta aatgttttag gatttgtaaa gaaagaaaaa gctagaaatc 107100tcaatgcaac tctgacttgt atgtcctgcc ataggaaggt ttgggacttt tctttggaag 107160atgggaggct tccttcacag tttcttaact tctcatttta ttcaatcttt ctccatctct 107220ctctctcttt ctctcatcct cacgctctct gtctgtctct ctcctgattt gtctgcttag 107280ggacagacag gtaatggaga agaaattgaa agggaaaata cagggaaaat gtaaatgaaa 107340agaagttatt ataactgtta taatgaagtg cctttcattt aaatataaga atgtaacgct 107400gaaatgaact tgtgatcctg aaatgcattt ttaatgagtt tcctttttat tttgctgctt 107460cagtggcata ttttaaagac cctttgaaaa aagccacatt aaaaaacccc accaaatgcc 107520acaacacgca aaattggata ttggtttatt ccaaaactgc tgatcaggaa gagtggctct 107580tcatcacaaa atgttgcagt cactttattt aaatgagttt gaatttgcat tgtgatgtgc 107640cattctgatt tagggaaaaa aaattagatt ttcagatcaa attgacccag ccagtgaagc 107700gttaaggagc tggcaggttt agtctgaaag cctcatgttc tatcaaacct gcagccggtg 107760gaagtcacca ggcccccgtg ggaaacaact ttctcgtagc atcgtcctca tgtccccacg 107820ctgagtttag ttctcaccag ctctcctctc tccgtcccag gagaacggcc cttccagtgc 107880aatcagtgcg gggcctcatt cacccagaag ggcaacctgc tccggcacat caagctgcat 107940tccggggaga agcccttcaa atgccacctc tgcaactacg cctgccgccg gagggacgcc 108000ctcactggcc acctgaggac gcactccggt aggtcccctg gatgcagtcc ggggctgtct 108060gggtgtcccg ggattcctcc actctgcccg cctgggtccc ggattgtgtc cttgctggct 108120aaccctgagt ccctcccagc tcgcagtcct gcatcgggtg tgagctgttg cttctttgac 108180attgccccat cccccctccc catattctcc ttttcccact gcaccaggga gattgggcgc 108240aggaccccca tgcacataca cacacagaag tctcacctta ggtagcatgt ttcagaacag 108300gcctcctcat cccgtttgtc aggctggtat ggtttcccta aaggattttg cgggaaatgt 108360tttcaccaag tgtactgcta agacccaaaa cgttttcaag tacaattctt tctgttgtta 108420agtcccgctt tggagtgttt tacacaggtg taatggatag cttttttgca gagctggtag 108480agaagggtga tttagggcgc acccacccag actgagcccc gtgtggctct cacaccaaaa 108540accagccaag gccacagtta cagaggccag tctggggctg ttaccagatt ttagacagca 108600gcctttctct ttgaattaga cagttaaagt acaacccaca taatctggag tcttgacaag 108660atcatcatag gcataaacgc tctatcattc tcaaaacagt ctcagcctgc aaagttcaaa 108720tccactaaag tttggttaga tcctctgcct cctgagaaat ggtcctgggt gtttcattat 108780ccagcagtcc cataattcta cagggcagag gaagagaggg ctcttggccg gcctgtcatg 108840gatcatgttt gcctacagtg tggtctatac aacatgacat ggcacaggtc tccttcatac 108900cgtccagttg gggatatttg ctgtagcata ctgcatgaga cttcggaggc gaaaggttga 108960tggcttttgt ccttcccctc aaggagcttc ctgccccagc cagccaccag ccagggccct 109020tctccaagca gcagcctctc taagccggtg ccctggggga tggcaatgcc tcagaccagc 109080tactcctcac ccaccctggg tagcaggata aggaggagcc tccctcaggg aggcagacgt 109140gtgttctttg tgaaatatct gcagcggccc aggccatctc ttcccaaatg tgatgcgtgt 109200atttgatggt tgagggtttt agaggctgct cattgtgtcc atctctttat cacacattta 109260ctgagcaccc ctgggtgccc attctgcaca gaagacctca ggtgcacaca aggaaagcac 109320caatgtgtta caggaggcat gacagagtgt ctgaggggac agtgggagca taaggaaggg 109380gacagtgggt cctggggtgg aaagtcagga gagacttccc atagaaggga ggggcttctg 109440aagtacatgc tggaaggcga gtgtctgagg tttgctttag agacattcta aactagtgtg 109500tgagtcggca gtaatcccag agaggggtgc ggcacccatg ttggcaagaa ctcggtctca 109560ctcctggcag gtggtccctg cagtagttca cccagttggc tggagacaaa aaggagagga 109620gtcacagggg ctggtgcatc acctcctctc catcctgacc tccttcctgg cggtgcacat 109680ggagaaggat ccccacatgc tcgccatcag aaaattgtca tgatttgggt gatttgactt 109740cctaaaaact tccaagaaag gagctatacc aagctgagga gttgcttgcc cgagagggcg 109800ggcagatcag caggggggcc atggagtggg acacttgcct tgttacagag ggacagggag 109860aacaggtggt tcccctgaga taggaagaca gtagcatgac ggtgagcatc tttaaatgtt 109920cacatgggtg atgagcatgt atggtggtcc cacctggaga caaaggtggt acctgggcct 109980gataagcaag gcccatggag gcctcagcta agagaactgt gcagtctgtc tgccatgcta 110040accagtggtc taggaagaag cttcacatct gttgtttcta aggagccatg tagacataga 110100cacagttggc agcaatattg ccttgggtta gtgggaagca ccacttccca tgtcagtgga 110160aaacacagac actcgttctt aggttgacac caaccatagg tcatcatcac tcctagatta 110220ctctgattgc aatggaatct ctcatgccca tcagtcctta aaagcagagc tgctctcttt 110280cctttcttgt tgtggagtta ggaacatgta gtggagtatt ttatgttatt ctggctccag 110340gcctatgtat ttcatttgag gcatgatggt ttcctattct aagtaccact aagtattgag 110400tagttataaa atggtggtag actttggact gtgtatttct attctggatc cacggatgag 110460caagtggaga aaacccatca tggatgcagg gctgctgggg atctgtctgt ccgaaaatgc 110520tatagagaca cacactgctc ttggggaaaa aaacagtgat gatttcttca aaatgatttc 110580actgaagtga aataaggact ttggccttgc tctggcaaat tcaaatgtgg ccacactcta 110640ctccattgtg gaatggtgac tcccctgtcc catgaaaaac caggatcaac atcacagctt 110700tctctagcaa ctggtggtgg cctgaggtct tatgaactag catgttagca gggatagagt 110760tagggaattt gtccgatgct gacagcaaga gggtgctggg ggagctggag gggtggagaa 110820gtgatctccc ttcctgcctc atggcttcct ttggaagttg caagcttaga atttctttcc 110880caaagaatat tggactatgc ttcaagagac acttgagttc agttgcttac agtgaacata 110940cttcttatgt tccagagtta aactcaatca tattttcaga aaaatagata ttcagacatc 111000atgtcatatt tacaggaagc tatttgatca tggaatttac tgaagtgaca

gctttttcag 111060gaaagggtat cgagtggtta tctatatcct attaatttct aaaagcaatg ctcaataaaa 111120tgtgcaattt taggcaatat tctgtgtttc aacattattt ccttatgttg ggggtacatc 111180actttatata gataaagaaa gatccttttc attctctatt aaatggtcga gaagtcaaat 111240tttggctttc atgttggtct tcttactgta gcttctgttc acctaagaaa gagatttaac 111300caacataagc tttggctaaa ccattgtacc aaacatttct atttggatgc tcttaacttt 111360tatacaatac tttgaaatgt gttcaataaa acaacatgag aaagaagtag aagattctgc 111420tattaggttg gaaattgata ttccttacat aagtgattaa agatacttta ttcagtttat 111480cccttaaaat ggtatctact gaagtcctta aacttaggca tgatattaat tcctggctag 111540tctttctttt tcctaaaata tcactcaata aaatccaaga aggactaaaa ctcattatat 111600agaactgcac tgcccaatac agcagccact agccacatgc agtattttta attataataa 111660gttaaaatta aacaaaatta aaacttcagc cctcagtggc actagccaca ctttttgtgt 111720ccaacagcta catatggctg gtggctgcca tattggacag cactaataga gagcatttct 111780atcatcatag gaagttctgt tgaacaaggc tgatctggaa gctacaccat cctaaagctc 111840tttggcaaga aagcagagct tttccataag ctcagtttat gaacaatata ttttgtattt 111900tctatgtata tgtatatgag aatacgtata catagaaata tatgaaaata catatacata 111960taaatataca tatacataaa atagaaatac atatacatag aaaatacaaa atattttgta 112020ttacatatac atatgcatgg aaatacaaaa tattttgtat tatataatgc aaatgtaaga 112080tatatttata ttatgtaaga aaatacattt gtgcaataaa acgcttattt cattcaagca 112140tatttgtcca gcatggtttc ttagagactg aagttaccca gtttagcacc tggaactgaa 112200ttcactctgg ctgtgttaga tgtagcacca gcgtcatgac agatccagcc cacagcatag 112260actgaggcct actctggagg caaatctgca gacaatgtgg ccaacacatg ggccttcctc 112320acatctctgt ccagtcgctg gcatccacgt tataacacag cagtggctcg ttttctccag 112380ttaaaggcta ggcttccgtg attgaagcag gagagaattt ggtagtcagt aaagtagaca 112440aactaagaca aaacaagagt cgcatgagtt cttggtacaa ttaaagaaac ccttggccac 112500caacgttttt aaattcagga atttcaccaa gtccgtaaca gttttagctc tcaagggtag 112560aatttttttt ttaacttttt tggtaataat tgtattgcat gcattcccct tacacagaag 112620gctggcattt aattggggtc ttgaactcaa ttgtgttttc tgcagttggt aaacctcaca 112680aatgtggata ttgtggccga agctataaac agcgaagctc tttagaggaa cataaagagc 112740gctgccacaa ctacttggaa agcatgggcc ttccgggcac actgtaccca ggtaagcgct 112800gctgctcgga ggccagcctg gtgggctctc cccccagcac ggtggggaag gagggcgctc 112860tgcatgcagc cttaggagca gagccttggg cctgcttcct gccggggcta ggagggaggg 112920aagtttttgg ccaatagcat cagtttcacc agaagcacgt tgtgcttccc agctttctag 112980gtcctcatct gaccagagag agcttgattt taaaaccctt cccacttcca atcgggagaa 113040actcctagga tagcagtgac cttgaaagtt ttggggttgt tttttggatg ttggtgattt 113100taaaacaaca acaaaaaaaa cacctcaagt agtgatattt ctttgtaaac aaaataaaat 113160gtaaaatatt gttttgaaac aattttttaa caaagttgat caaataagaa ctttcaggct 113220gtgattttaa gcatcagttc agactgaggg cagggtatcc actcctgcat ggagtgtgag 113280gttgaagttt gttggaagcc cctggtagtt gataatattg aggttgttga aggatgagag 113340gaaaggtcgc ttctttctta ggagctgtga tgctccactg tattgcataa cgagatagca 113400cttgattcag accccagagc ctgtagaata aatgatgtgg agagagtatt gaaaaaggct 113460ggatttatct gggggaatgg caatgttata aaaggttctt ccctaatttt ttaagagata 113520agcaatttat aaagagatca aataaaacta atctctttca aaacagtatt catttagcac 113580tacccctgga aaaatcatca ctagactgtg agtcgaaatt taacgaatgg aggaaaattt 113640attaagcctc attcaccttt cggactttaa caaatggttc aaaagggaaa attcaccaga 113700gtaccctcag attattaatg gcagatgaga gcaggaaaaa agaatgttga gaatggctaa 113760aaattgattc caattagtct tggcatggag aggcaacatc tcacctggcc agagccctgc 113820agccagagtg ctgtctcctc tgccagtcag ccagggatct ggggcttaca ggcgattcct 113880ccaggcctca atcttctcac ctgtgaaatg ggaagatacc attaaattgt catttggctt 113940ctttcaaaat ctcaggtcta gaatggaaag gcattgaagg tgagtggaag agaagaaact 114000ggatgttaaa ataataataa tgtaacagtt attaattcac atggccagac cccagggcag 114060aagactaatg gacgagagga tgattatgtt cctttgaaat aaaatgtcaa cattcaaata 114120ttgttttttt ctgtaaaaaa taagtgaatg ggtcttggaa ggaagtgctc ctaatgatgt 114180agtttacata ttaatgctta ataaaccatt ttatttactc aacaaatatt cactgaggac 114240ttataatcaa taataccaag ccctattgaa tacagtaatc taatatacac atagaattga 114300aaagacaaaa tgaacaaaag aaacagacag tatatcattt ctgtttcctc cactgttttc 114360attactaaag aaacaagctg cagtacacag ccggctgaga gctgcttccg ggggagcagg 114420agaagcagca ctcatttcac tgagacctgg gtttgagttc tctgtttttg aatgtgaccc 114480agagctcatc gcttaaatgc gactgataat tcgtgcctgg ccaccctcat agcagcgctc 114540tgaaagaaac ataaaggagt ggatacacgt gtgagcagga gcctagacat gtgtcaggta 114600cttacctaaa catggatgtt taggtcactg acatactgac accatcaagc taattcttct 114660ctattggtct ctatgtcagt aaggctacgt gccagtaatg tgtattaaat attaccctgt 114720ggtgagtatc aatttcaccc taaaatgttc atttattccc tttggtggtt aagttacttg 114780gactaccaca gtgatgcctc tatgtcccca cactcaggag gtatgaaagc gtctctagga 114840aggagcagtg gtctggtctc agtgtggcag cagacaaagc caggctcgca cttaattaca 114900ttgaattatt tctgtctggt atggcctcaa aaggtgcaaa atgatcataa atatctttcg 114960acagtcacct ttggtttttg cccttgccag cacctggccc ttgtaggtgc tgctggttta 115020aggaacttgg agtattaagg ggatccataa aaggactttg acagaagtct tcctgaactg 115080tgcttagggc caggaaggca ggcaggggct tggtcatttc agctgtgctg tacccggatg 115140agtggaaact gtgccttctg atgcatctct cctcctctgt tcccctctaa gaaccccttg 115200tctgtgctca gatggatgag caagtagtct cttctcccac cccaaaaacc tccttagatg 115260gggtggattc agtaaaatca aagcctcagt taggcaatat aggaaaagat gaatttttgt 115320gaatataatt ttctttagta aaaggctttt ggtcacctct tataatttct caatgtcttt 115380atggaaaaaa taagtttctc ttgagccttt ggtgcacaaa cagagtcacc agcccttgga 115440ggtgcatgca tctaatgaca gagcagcctg tgactcgcga gcatcaggct cacttgttcc 115500ttgctgtgat tgactctggg gggtggaggc ttttgggagg ccctgcgcca tggtgcagag 115560gaagacccct gacctctggg agccctgggc aggctgtggg tgtggcttgg cagagaagga 115620tggacatgtc aggaagcata ttagcttaat agatgaagtg tgtgaccagt gtaattgggt 115680tttatggatt tatatttatc ttgcatataa atcagggtgt ggcctatata tgtttgccca 115740tttaataaaa aacacatatt ccaaatgtta aaatataaaa tataccagca acaatagcca 115800atttgaaata tatgttttca aagtaacatt cataatagca atgaagacat aaatacttag 115860aaatgaagaa aaccagcaag ccatagtgag gcaagaaaga aaacatggga gattggagag 115920gtagagaggt ctggatgccg tccatgggcc tctgcccaaa ttagtgtatc atttcaacat 115980aaaactggct tgtaaatttt actggaatct ggtaaccatg tatcataaag tatctggata 116040tatacatgag ataattggca actttttaga agaagaataa tgtcaagtga tgtatgaaaa 116100tgtagctgaa atggatggaa ctctttgaag aatagacaaa caaatcaata atagagatgg 116160ataccctact gaagacccca tgataaatca gcatgaaata tccgaggcag gaggaagcat 116220aaggcaggaa cggtattgga agaattgatc aggcatttaa gataatcagt ttacattatc 116280atctccttat acactaggat aaattgccgg gaaatgaaag agttatattt ttataactcc 116340aaccacaata actgatgtaa atatagatcc agctatgcag gatacaaagt tgtatcttca 116400attatggaaa gagatgacat agaacaattg agaatgacta gaaatggccc acacatcagc 116460atttacctcc ataatttcta aattttctac agcagtcagg ggtgctttga ttttcaggag 116520tttgttgtat gctcagggat aaggggctct gggtttttcc tccacattgc ccagatctgc 116580tgtaggctct tgggggccac atttttgtat ctccgttcac tgtgctggtc catgaagtca 116640gatgttagat cacacagttc tttgcgtctc agagggctgc tgttagggac tgactgaggt 116700agcagatttg ggagtattat gaaaagttaa aaggacttgt caaagggaca tcaatactta 116760atcccagtcc agcctctggt gatggtggtg gtgcctgtgc atttggactt aaagaggatg 116820atgtgtggtg agcagctgtt ggaggaagaa gcatttgcag gtggctggtc attggcattg 116880ctccggctgc ctctgcctgt ctggaagtgt tgctgggaag attagaatta atctctagga 116940agggcctggc tcttgtaggc acttaacaaa tgtcagattt aacattggac gcgactgaac 117000cctttaaaca taagcctttc taaactggcc tctctgtctt tgactttagt cattaaagaa 117060gaaactaatc acagtgaaat ggcagaagac ctgtgcaaga taggatcaga gagatctctc 117120gtgctggaca gactagcaag taacgtcgcc aaacgtaaga gctctatgcc tcagaaattt 117180cttggtaaga gttaaatgtt tgctgtctct taaaaaaaaa ctatgtgggt gttttagatg 117240caagtagaaa tgagttgagg gtggaagaaa gggaaaaaaa tcttattttt tcaaaaggaa 117300aaattggtaa gcttaacatt ccttaaatat cttagaattt tttccaataa gtatcttaaa 117360aataacaaac ctcccatcag tttttcctag atttgatttt gcagcatctg gggcctgccc 117420tgtgatctgc ctgtggacat cgctcttagg ggcggctgca ccagcgtgca cagggtggag 117480agtttgggcc tggctcgtcc gggggacacc acactgcagg acactccagg cctggccggc 117540ttctcagagc ttcagatcct catttttcat atgaagctcc taatgctccc cttatggggg 117600actctgaagg gttaatggga ggaatcatac agtgactgac ccctgagaag tgtccagtga 117660agacagggct tagctaggat tgctgttttg cctaatgctc tgcgggatta aaaaaaaaga 117720agaagaagaa caagaccatt cgtctctcta ggagcattgc ccagagtagg tattagacac 117780accaacacca ccatccagcc agacgctgca gggacagtga gccagggtcc gagtggaaag 117840gcgctaggct tgggaaccag ctcagagtca atacagagcc accgccactc accaactctg 117900tcagcttagt aaaatggctc tgcccctaga gccctggttc catcctttag tatctcacag 117960ggtgattgtg aatatcccat gactccaaga ttgagaaaac gtttagaatc cctcggtgtg 118020aaggttaact ctgtccggaa agaggaccag taaaagcttc atgaggctga gatgcacttt 118080ggaagaggaa tagagtttca gcacattcta ggtgttggag gaatggggga atctaggcag 118140atgtttaaaa tcaatgagaa accagaatgc tgaccatgag ggttggagtg ggggcctaag 118200gacatgacgg aggagcaggg tgtgttccca gcttaactca ggtacccatg gggaagcagg 118260aaaagtgaag gtgtcctagg cagctctgcc acaggatgaa tggcttcaga tgccaggtga 118320gcgagggacc cttcattcag tcagcaggaa agaagcactg gcatattttt tatgagaaca 118380aaggctagga tagtaaagac agcaagtacc aaaaaatgac tggaaaaggg agactgtgga 118440ggcagtggca gcaggcatgg aaagaagggc ttgtgaaggg gaaggggtgg tgtcagagga 118500acatagggct gggggcaggg attaggtgag ggaaaccatg agtcacactg attctagagt 118560agtgtgccct tgatgaaaag gataacacca ggttctagga aaagatgggg ttctgttttt 118620gacgtgttga ttttcaagga cttctggtgt ttgtgacaca tggggaaatt gtggtgggag 118680agaggtgggg ccagaacagg ggctggtgag gccaagggtc ccagagggca cctgttgacc 118740tgcaggatga catgaagggg gaaggacaga ggcaaggcca agtcctgggc accagcctcc 118800ctcttgcagc ttcaaatagg gctccatttt gaccttttga ttaattagag gtttgtcata 118860ggttgggggt tgagaggagc aagggagaga aggattcagt gtacaaaaag aatgaaagcc 118920actggctgag ccagtgggga gttgtccaca cacacatgag cctttggacc atgagaacga 118980gggaggcctt gccttcctga acggagtagg agtgaggtcc tgtgctgagc gtaagcagtg 119040ggattcccac agcactgggc acagagccca cgggctgcct cctgagcagc cagcatctgc 119100ctggggtgga cacagtgaca gagagatggg tggtgactgg ggtatgggca gagataaggc 119160agcaagtgtg tgcaagggga gtgaagggtt actgacctta agaagcaggg atggcgtcct 119220ctgtcaggtg aggagcctgg agaatgcttt ggtgaatgaa cgtttgcagc cccttttagc 119280ttttggagac ttgaaaccaa aggagagatt catctgtgaa actctactgg agccactccc 119340caacccccac ccttgtgaga ccacaatgtg ggcgttggct tgagatgctt ctgtgttagt 119400agaagaaata aacaacacag tgctctgatg aggcaaagcg aagatgaaaa aggagttccc 119460aggggacata gtaggaacag tggacgaggg tagcagaaga ggagtttgga gcaaaagact 119520cacaagcagc tgcataatct gttggtgctt ggcagttcat ttgtaaaaat gatgcctctt 119580cctgccctaa aatacctacc ttacccccgc ttcaacttga tgagatttcc atcagtcact 119640cccaatgtgt cacagcttct gcagccctaa aattaaaagg tgagtgagtc tctgaggccc 119700ctctccactt ctcggatgct gagtttagcc ttcatgtgaa tgtggaaaga ctaggaatac 119760agctgttatc acacaagctg gcccaatagt ggttcagttg agagagcccc atccttcaga 119820gtcagctcca gctaggagtg actggtggcc ttgagcatgg tgctgggctt agtgttgcca 119880tctgtggaat gggtgtgggt ctgttgccct gcctcctccc agagctattc tgaggctcag 119940aaggggtgat ggatgtgatg gtgctcccaa cactagaaag catcttaaga atgtaagatt 120000ttcatgatga ctgttgctca gagtggctat tatagttttg ctttattgtt ctataaccta 120060tgattaaaat ttttacctta aactttgacg tgagtgtgaa taagtatttg ttttgccagc 120120aacattcctc accactgggg ccattaaaga tctccccctc tgagaccatc aaatacaggt 120180caacaggact gattaatcta attagaaaag ggcttgtatt aaatagcaat gataattgtt 120240gtttttagtc tgtctggtgt ttgacttggg aacgttttta aaatagagaa aagcacaaag 120300aggaaaacaa caattaccaa tattcctgct acccattata attatctagg tatattttct 120360tcttttgtaa gaaaaagaaa ccctgttata ttgttaaaat aacacaaagt taatataaag 120420aattttaatg caaagattaa tgttttcaaa tcaccacaaa acccaacatc cagaaattac 120480caatattaaa agtagaaaag tatcattcta aatattttct gttgcatatg tatgtgagtg 120540gataggctga tgaattaggt ggattgatgg ataggtaaat atgaaataaa tactttcata 120600aatattccaa cttatcatac atgccttaaa ttcaagaggt gaaaaaagac ccaaacaaaa 120660ctagagaagc ggcttatttt aaatatcctc tgacataaag gaatattata tttaaaggat 120720cctctaagat taaaaatatg tactatgaaa aacattaaga aatttgaatt ttttttaatc 120780catttgtttc aatttaagca gcatctactg gctcactgct ttgaaaaata aggacagtat 120840tccagttcac attcagtgtt ccagtgttca cattatctta ttatttttac attgtccagc 120900tttgtaatat tcacattcta ttctgtaatc ataattcata gtagtttagt tatttattac 120960taactctatt taaatagatt caaggatcag accctgccct tttcttctta tttatgttta 121020ttttgattaa tctcttaatt gattggactt tacattcaag caactttttt aaaaaaaagt 121080ttctatagat gttctatttc tatcattgta ttgtttttga ggatgttggc ctgttgcctt 121140tgtatttgat gagcattttg acagagtcta tggtcttggg ccactctttc tttttctccc 121200ttgagaactt tttagatttt gctgatggca ttgcttgttg aatgttgctg tggaaacatc 121260aagtctagtg taactgtttc ttcttcaagg tgatttgcat tttattcctg aatgcctgag 121320ggttctttat ttaaccttga agttaaatac cctaattagg atgtatcttg gtctattcat 121380tcggaataaa aaattcctgc cattttgtct agagagtccc ttttttttct ctttatttct 121440gggaaattct cttttatata aatatgtttt gttccatcta ttgtgatctc tgttgaggga 121500taccagttgt ccatatgtta gataatttgt cttccatatc tgttaacagt tcttaaagtt 121560ttttgtttat ttctttgtct atttttacat ttactcactg ttctcttgtg gttttcctct 121620gtcagtaatt taatttttag tagttcctgt tctattactt gctattttta atccatgcat 121680taattttata ataatattat tttgctcctt attttgtctc ctgagacccg aaatctcttt 121740tttcctctta ctctgttgct tttgcatttt attttgaata cttttaaaat tgattccatg 121800ttatgaagca attatgaggc atttcctctc ttgttggaat taacgatttt ttcccctagg 121860agggactcta tggtctgtgt tttacttcct ttcttcccct gtatttctag aaaatatttt 121920cctagtaacc ctgacatttc ttttcatctt gcttattcta gttggtctga tatagcttga 121980ttgacatttc agccttcttc ccactatatt tttttttcct gtgagagcta ttgggttttc 122040taaatcctga aagaatgcca aagatggggt tggaggagtt tggtgaggca aagtgcagcc 122100tttgttaaaa tacttttcct ttgctctctc tccctcatct gaaatttagt taaataccct 122160aagccatcag cactgtacct agttggggaa tgctttcatc cccacaggag attctctggg 122220gctttgggcc atcttcccct tcagtgtaga ccacagagga ctttgcttct gtcccaggga 122280gcccgcaggg gctcacttct ccatgttcat ctgattcttg tcagccaagg tttcaaatgc 122340ttttctgatc agaacaggga aaagatacct atctgaatca tgtctttata gatatgaggc 122400tatgagggaa aattctgagg ttattcttga ctcacaccta aagatttgga aatgagatta 122460gcagcaaagc tttgccctac atctcatgtc agaattttct gtttctttct agtctttgag 122520tgtatgtgtg ttctcacaca cgccataatg aaatgcatat tatatataat tatgtgtata 122580tataatattc tatgactata catgacatgt tcctttagct gattgctgtt aagagaaatt 122640tataggtttt tatttttctt gttttgttgg gtattaagga agagaaattc tatggtaatt 122700ttcatgtggc acagtaatct ggcatatatg ttgatttttt tcctacaccc atttgttgtg 122760ataccaagtt tgaaaacaac agatttcagt ggttgcttgg gaaaccacag aaccatgact 122820tggggagaga caggatgatt aggtgggaaa gcaccctttt ggtggggctg taaagacttt 122880tatatttagc aaaattggct acaaagtcca ttcccctcct tttcttgcct tgatttggta 122940gagggataga cttggataca aactagaatg gattcattct tctctggagt tagtgtaaca 123000agacatttag ctgctcaaca caaaaacaga aacaaaaaaa ttgtgtggtt tcagcagtgc 123060tatacaatta ctttttctga cctttaatgg agagaaacac cacttctttg gtccctacca 123120tcagcttcat agggttttca tcctgttctg tttctgggag ggcgtaactg gccatgcaca 123180agtttttttt ctctaatcag agtatgtgcc acttctgacc accagtagat gaaaacgaat 123240ggaaaccagg ctattatatg atacatatcc attacaaaat aagacatgaa actcaaaggt 123300actttatggt ataatggggc atatattcct ggacaattct taatggtcac agattttata 123360aaaggactat tagtaaatgt atgaattaca gagtaattta tccttctgtt agtaagaacc 123420agctgatgac ctcagtgtca ggtgcatcgt ggaaggtgtt gggaccttcc cttgccacca 123480ccctcaccag ccatcatcag ccataacctg cacattgggg aagttttgac ttatccctca 123540cttttgcccc tcttcaagct gttctttcca cagtgaatga gaaggccact tcttccttca 123600aacctttcag tggtttccat tttcctttag acaaagtctc tgcctagctg gcctctgcct 123660gcccctcctg cctacctctc gagcactgcc cccacctagg gctctggttc cccaaccttc 123720actcggtcct gccacacctc ccagcccctt ctcccttcag aactttcctt cttgttgtcc 123780ccaacactgg gacacaaaac cctccttatc aaccctcctt atctggctga ctcttacaag 123840atcagaaacc tgtgtaatgc tctcatggca cgctcccctt gtcttcgtgg atttctcaga 123900tgggaaggaa ttatccatgc aatcacacat aaacttctac ctaccctccc ctagtagctg 123960tctgctgcta aggatgggga ccattctcac ttactcactg ttctgtccct ctgcccagtc 124020cagatgtgtt gaaggatgga aatatacaga gtagtggtaa aatataaacc gttcagacat 124080tccaaggatg ggctcatgtg ctttgactca ttaatgtacc actgctgaaa acagaacaca 124140gccgcagtct tgccagtaag agtgcagtta ctgtaattaa tgaatttgct aattaagcca 124200tgatttcata ctgaacttat gaccaacata ttgagaaggt gtgtcttcaa gaaaatttat 124260tttttgtatt aagatattta ctccaaagct aattgaagaa gccaaatcta ggctctggtt 124320tcaccattgc cagggaaatg agctcatgga ctcctatgaa ctgatgatgt tagatcagaa 124380gtttctcaag gccagggccc aatcactgct gaggcgtcaa cagtagttcc ttgtacatca 124440ataattctca ttacttttaa aaaataacag atgaatagca actattttcc ctgtagctcc 124500cttgctgtgc ctcctaccct ccaccacatg tttctgggga gccctgcttc gggcctgcca 124560actacagaga attacttttg agtatccctt ccactctcat ctcaagacag agttcatcta 124620cctttgggtt atttgtcaaa aatgtgtcat tttattacaa aaaatataca atcatcatgt 124680attttgatta aattttacac tagattatta aaattattaa atacaattat taaaattaat 124740aatttaacat atcacatatt ttaaatatat tgtatataat gaataataat ataattattg 124800tctattttaa ttcaataaat gtatagtaag ttagccagtt gtaaattact gagaacactc 124860tactgaaaaa gcatcatttc aaatacacta tttaaaatat taaatgaaat acaataacat 124920aattaaacta atctttggtt cccctattta tgtattcatt tatccaacaa aatctcctta 124980agtgcttata atgggtaggt cctggctcgg tgtcccctag acagacgcat gggccttccc 125040ccagcccgtc agtatggtgc aggtgtgatg tgtccgcagg tgtgtgtgta tgtgtgcagg 125100tgtggggtcc gcaggcgtgc tgggccccca ggccgtgttc cccttcccct ccccggttgt 125160agatttcagc tgttgctgcc agacctgacc ggttccggag gtggccgcgc cccactcact 125220gtcgcctgct ttccacaggg gacaagggcc tgtccgacac gccctacgac agcagcgcca 125280gctacgagaa ggagaacgaa atgatgaagt cccacgtgat ggaccaagcc atcaacaacg 125340ccatcaacta cctgggggcc gagtccctgc gcccgctggt gcagacgccc ccgggcggtt 125400ccgaggtggt cccggtcatc agcccgatgt accagctgca caagccgctc gcggagggca 125460ccccgcgctc caaccactcg gcccaggaca gcgccgtgga gaacctgctg ctgctctcca 125520aggccaagtt ggtgccctcg gagcgcgagg cgtccccgag caacagctgc caagactcca 125580cggacaccga gagcaacaac gaggagcagc gcagcggtct catctacctg accaaccaca 125640tcgccccgca cgcgcgcaac gggctgtcgc tcaaggagga gcaccgcgcc tacgacctgc 125700tgcgcgccgc ctccgagaac tcgcaggacg cgctccgcgt ggtcagcacc agcggggagc 125760agatgaaggt gtacaagtgc gaacactgcc gggtgctctt cctggatcac gtcatgtaca 125820ccatccacat gggctgccac ggcttccgtg atccttttga gtgcaacatg tgcggctacc 125880acagccagga ccggtacgag ttctcgtcgc acataacgcg aggggagcac cgcttccaca 125940tgagctaaag ccctcccgcg cccccacccc agaccccgag ccaccccagg aaaagcacaa 126000ggactgccgc cttctcgctc ccgccagcag catagactgg actggaccag acaatgttgt 126060gtttggattt gtaactgttt tttgtttttt gtttgagttg gttgattggg

gtttgatttg 126120cttttgaaaa gatttttatt tttagaggca gggctgcatt gggagcatcc agaactgcta 126180ccttcctaga tgtttcccca gaccgctggc tgagattccc tcacctgtcg cttcctagaa 126240tccccttctc caaacgatta gtctaaattt tcagagagaa atagataaaa cacgccacag 126300cctgggaagg agcgtgctct accctgtgct aagcacgggg ttcgcgcacc aggtgtcttt 126360ttccagtccc cagaagcaga gagcacagcc cctgctgtgt gggtctgcag gtgagcagac 126420aggacaggtg tgccgccacc caagtgccaa gacacagcag ggccaacaac ctgtgcccag 126480gccagcttcg agctacatgc atctagggcg gagaggctgc acttgtgaga gaaaatacta 126540tttcaagtca tattctgcgt aggaaaatga attggttggg gaaagtcgtg tctgtcagac 126600tgccctgggt ggagggagac gccgggctag agcctttggg atcgtcctgg attcactggc 126660tttgcggagg ctgctcagat ggcctgagcc tcccgaggct tgctgccccg taggaggaga 126720ctgtcttccc gtgggcatat ctggggagcc ctgttccccg ctttttcact cccatacctt 126780taatggcccc caaaatctgt cactacaatt taaacaccag tcccgaaatt tggatcttct 126840ttctttttga atctctcaaa cggcaacatt cctcagaaac caaagcttta tttcaaatct 126900cttccttccc tggctggttc catctagtac cagaggcctc ttttcctgaa gaaatccaat 126960cctagccctc attttaatta tgtacatctg tttgtagcca caagcctgaa tttctcagtg 127020ttggtaagtt tctttaccta ccctcactat atattattct cgttttaaaa cccataaagg 127080agtgatttag aacagtcatt aattttcaac tcaatgaaat atgtgaagcc cagcatctct 127140gttgctaaca cacagagctc acctgtttga aaccaagctt tcaaacatgt tgaagctctt 127200tactgtaaag gcaagccagc atgtgtgtcc acacatacat aggatggctg gctctgcacc 127260tgtaggatat tggaatgcac agggcaattg agggactgag ccagaccttc ggagagtaat 127320gccaccagat cccctaggaa agaggaggca aatggcactg caggtgagaa ccccgcccat 127380ccgtgctatg acatggaggc actgaagccc gaggaaggtg tgtggagatt ctaatcccaa 127440caagcaaggg tctccttcaa gattaatgct atcaatcatt aaggtcatta ctctcaacca 127500cctaggcaat gaagaatata ccatttcaaa tatttacagt acttgtcttc accaacactg 127560tcccaaggtg aaatgaagca acagagagga aattgtacat aagtacctca gcatttaatc 127620caaacagggg ttcttagtct cagcactatg acattttggg ctgactactt atttgttagg 127680cgggagctct cctgtgcatt gtaggataat tagcagtatc cctggtggct acccaataga 127740cgccagtagc accccgaatt gacaacccaa actctccaga catcaccaac tgtcccctgc 127800gaggagaaat cactcctggg ggagaaccac tgacccaaat gaattctaaa ccaatcaaat 127860gtctgggaag ccctccaaga aaaaaaatag aaaagcactt gaagaatatt cccaatattc 127920ccggtcagca gtatcaaggc tgacttgtgt tcatgtggag tcattataaa ttctataaat 127980caattattcc ccttcggtct taaaaatata tttcctcata aacatttgag ttttgttgaa 128040aagatggagt ttacaaagat accattcttg agtcatggat ttctctgctc acagaagggt 128100gtggcatttg gaaacgggaa taaacaaaat tgctgcacca atgcactgag tgaaggaaga 128160gagacagagg atcaagggct ttagacagca ctccttcaat atgcaatcac agagaaagat 128220gcgccttatc caagttaata tctctaaggt gagagccttc ttagagtcag tttgttgcaa 128280atttcaccta ctctgttctt ttccatccat ccccctgagt cagttggttg aagggagtta 128340ttttttcaag tggaattcaa acaaagctca aaccagaact gtaaatagtg attgcaggaa 128400ttcttttcta aactgctttg ccctttcctc tcactgcctt ttatagccaa tataaatgtc 128460tctttgcaca ccttttgttg tggttttata ttgtaacacc atttttcttt gaaactattg 128520tatttaaagt aaggtttcat attatgtcag caagtaatta acttatgttt aaaaggtggc 128580catatcatgt accaaaagtt gctgaagttt ctcttctagc tggtaaagta ggagtttgca 128640tgacttcaca ctttttttgc gtagtttctt ctgttgtatg atggcgtgag tgtgtgtctt 128700gggtaccgct gtgtactact gtgtgcctag attccatgca ctctcgttgt gtttgaagta 128760aatattggag accggagggt aacaggttgg cctgttgatt acagctagta atcgctgtgt 128820cttgttccgc cccctccctg acaccccagc ttcccaggat gtggaaagcc tggatctcag 128880ctccttgccc catatccctt ctgtaatttg tacctaaaga gtgtgattat cctaattcaa 128940gagtcactaa aactcatcac attatcattg catatcagca aagggtaaag tcctagcacc 129000aattgcttca cataccagca tgttccattt ccaatttaga attagccaca taataaaatc 129060ttagaatctt ccttgagaaa gagctgcctg agatgtagtt ttgttatatg gttccccacc 129120gaccattttt gtgctttttt cttgttttgt tttgttttga ctgcactgtg agttttgtag 129180tgtcctcttc ttgccaaaac aaacgcgaga tgaactggac ttatgtagac aaatcgtgat 129240gccagtgtat ccttcctttc ttcagttcca gcaataatga atggtcaact tttttaaaat 129300ctagatctct ctcattcatt tcaatgtatt tttactttaa gatgaaccaa aattattaga 129360cttatttaag atgtacaggc atcagaaaaa agaagcacat aatgcttttg gtgcgatggc 129420actcactgtg aacatgtgta accacatatt aatatgcaat attgtttcca atactttcta 129480atacagtttt ttataatgtt gtgtgtggtg attgttcagg tcgaatctgt tgtatccagt 129540acagctttag gtcttcagct gcccttctgg cgagtacatg cacaggattg taaatgagaa 129600atgcagtcat atttccagtc tgcctctatg atgatgttaa attattgctg tttagctgtg 129660aacaagggat gtaccactgg aggaatagag tatccttttg tacacatttt gaaatgcttc 129720ttctgtagtg atagaacaaa taaatgcaac gaatactctg tctgccctat cccgtgaagt 129780ccacactggc gtaagagaag gcccagcaga gcaggaatct gcctagactt tctcccaatg 129840agatcccaat atgagaggga gaagagatgg gcctcaggac agctgcaata ccacttggga 129900acacatgtgg tgtcttgatg tggccagcgc agcagttcag cacaacgtac ctcccatcta 129960caacagtgct ggacgtggga attctaagtc ccagtcttga gggtgggtgg agatggaggg 130020caacaagaga tacatttcca gttctccact gcagcatgct tcagtcattc tgtgagtggc 130080cgggcccagg gccctcacaa tttcactacc ttgtctttta catagtcata agaattatcc 130140tcaacatagc cttttgacgc tgtaaatctt gagtattcat ttaccctttt ctgatctcct 130200ggaaacagct gcctgcctgc attgcacttc tcttcccgag gagtggggta aatttaaaag 130260tcaagttata gtttggatgt tagtatagaa ttttgaaatt gggaattaaa aatcaggact 130320ggggactggg agaccaaaaa tttctgatcc catttctgat ggatgtgtca caccttttct 130380gtcaaaataa aatgtcttgg aggttatgac tccttggtga a 130421

Claims

1. (canceled)

2. A method of assessing the methylation status of DNA present in a biological sample obtained from a human individual at risk of developing or of recurrence of, or suffering from, a large intestine neoplasm, comprising: assessing the methylation status of an IKZF1 gene by measuring the methylation status of one or more DNA subregions located within the IKZF1 gene, by performing a bisulfite conversion of the one or more DNA subregions, amplifying the bisulfite converted IKZF1 DNA subregions or the complement thereof with oligonucleotides comprising a nucleic acid sequence that is complementary to the bisulfite converted IKZF1 DNA subregions under selective hybridization conditions, and measuring the methylation status of one or more cytosines in the one or more DNA subregions; and assessing the methylation status of a IRF4 gene by measuring the methylation status of one or more DNA subregions located within the IRF4 gene, by performing a bisulfite conversion of the one or more DNA subregions, amplifying the bisulfite converted IRF4 DNA subregions or the complement thereof with oligonucleotides comprising a nucleic acid sequence that is complementary to the bisulfite converted IRF4 DNA subregions under selective hybridization conditions, and measuring the methylation status of one or more cytosines in the one or more DNA subregions.

3. The method of claim 2, wherein the one or more DNA subregions located within the IKZF1 gene are SEQ ID NO: 3 or SEQ ID NO: 4 or the complements thereof.

4. The method of claim 2, wherein the one or more DNA subregions located within the IRF4 gene is SEQ ID NO: 5 or the complement thereof.

5. The method of claim 2, wherein the one or more DNA subregions located within the IKZF1 gene is within a nucleic acid sequence as set forth in SEQ ID NO: 3; and the one or more DNA subregions located within the IRF4 gene is within a nucleic acid sequence as set forth in SEQ ID NO: 5.

6. The method of claim 2, wherein measuring the methylation status of the one or more DNA subregions located within the IKZF1 gene comprises measuring the methylation of one or more cytosine residues in the gene region encompassing IKZF 1; and measuring the methylation status of the one or more DNA subregions located within the IRF4 gene comprises measuring the methylation of one or more cytosine residues in the gene region encompassing IRF4.

7. The method of claim 2, wherein measuring the methylation status of the one or more DNA subregions located within the IKZF1 gene consists of measuring the methylation of one or more cytosine residues on the plus strand selected from: TABLE-US-00012 chr7:50343869 chr7:50343872 chr7:50343883 chr7:50343889 chr7:50343890 chr7:50343897 chr7:50343907 chr7:50343909 chr7:50343914 chr7:50343934 chr7:50343939 chr7:50343950 chr7:50343959 chr7:50343805 chr7:50343822 chr7:50343824 chr7:50343826 chr7:50343829 chr7:50343831 chr7:50343833 chr7:50343838 chr7:50343847 chr7:50343850 chr7:50343858 or chr7:50343864

or a corresponding cytosine residue at position n+1 on the opposite strand.

8. The method of claim 2, wherein the large intestine neoplasm is an adenoma or an adenocarcinoma.

9. The method of claim 2, wherein the large intestine neoplasm is a colorectal neoplasia.

10. The method of claim 2, wherein the biological sample is selected from a fecal sample, enema wash, surgical resection, tissue biopsy, or blood sample.

11. The method of claim 2, wherein the biological sample is a plasma sample.

12. The method of claim 2, further comprising administering a cancer treatment to the individual when methylation is measured at one or more cytosines in at least one of the DNA subregions.

13. The method of claim 2, wherein the oligonucleotides comprising a nucleic acid sequence that is complementary to the bisulfite converted IKZF1 DNA subregions comprise a sequence as set forth in SEQ ID NO: 18 and SEQ ID NO: 23.

14. The method of claim 2, wherein the oligonucleotides comprising a nucleic acid sequence that is complementary to the bisulfite converted IRF4 DNA subregions comprise a sequence as set forth in SEQ ID NO: 16 and SEQ ID NO: 21.

15. A method of treating a human individual suffering from or at risk of developing or of recurrence of a large intestine neoplasm, comprising: assessing the methylation status of an IKZF1 gene by measuring the methylation status of one or more DNA subregions located within the IKZF1 gene, wherein the subregions are SEQ ID NO: 3 or SEQ ID NO: 4 or the complements thereof, by performing a bisulfite conversion of the one or more DNA subregions, amplifying the bisulfite converted IKZF1 DNA subregions or the complement thereof with oligonucleotides comprising a nucleic acid sequence that is complementary to the bisulfite converted IKZF1 DNA subregions under selective hybridization conditions, and measuring the methylation status of one or more cytosines in the DNA subregions; and assessing the methylation status of a IRF4 gene by measuring the methylation status of one or more DNA subregions located within the IRF4 gene, wherein the subregions are SEQ ID NO: 5 or the complements thereof, by performing a bisulfite conversion of the one or more DNA subregions, amplifying the bisulfite converted IRF4 DNA subregions or the complement thereof with oligonucleotides comprising a nucleic acid sequence that is complementary to the bisulfite converted IRF4 DNA subregions under selective hybridization conditions, and measuring the methylation status of one or more cytosines in the DNA subregion; and administering a cancer treatment to the human individual, wherein the human individual has: a methylated IKZF1 DNA subregion that is SEQ ID NO: 3 and/or 4; and/or a methylated IRF4 DNA subregion that is SEQ ID NO: 5.

16. The method of claim 15, further comprising assessing a post-treatment methylation status of DNA present in a biological sample obtained from the individual at a time point subsequent to said administering, comprising: measuring a methylation status of an IKZF1 DNA subregion that is SEQ ID NO: 3 by performing a bisulfite conversion of the DNA subregion, amplifying the bisulfite converted IKZF1 DNA subregion with oligonucleotides that are SEQ ID NO: 18 and SEQ ID NO: 23, and measuring the methylation status of one or more cytosines in the DNA subregion; and measuring a methylation status of a IRF4 DNA subregion that is SEQ ID NO: 5 by performing a bisulfite conversion of the DNA subregion, amplifying the bisulfite converted IRF4 DNA subregion with oligonucleotides that are SEQ ID NO: 16 and SEQ ID NO: 21, and measuring the methylation status of one or more cytosines in the DNA subregion.

17. A method of monitoring the methylation status of DNA in a sample from a human individual suffering from or at risk of developing or of recurrence of a large intestine neoplasm, comprising: assessing a first methylation status of DNA present in a first biological sample obtained at a first time point from a human individual suffering from or at risk of developing a large intestine neoplasm, comprising: measuring a first methylation level status of a DNA subregion located within the IKZF1 gene, wherein the subregion is SEQ ID NO: 3 or SEQ ID NO: 4 or the complement thereof, by performing a bisulfite conversion of the DNA subregion, amplifying the bisulfite converted IKZF1 DNA subregion or the complement thereof with oligonucleotides comprising a nucleic acid sequence that is complementary to the bisulfite converted IKZF1 DNA subregion under selective hybridization conditions, and measuring the methylation status of one or more cytosines in the DNA subregion; and measuring a first methylation status of a DNA subregion located within the IRF4 gene, wherein the subregion is SEQ ID NO: 5 or the complement thereof, by performing a bisulfite conversion of the DNA subregion, amplifying the bisulfite converted IRF4 DNA subregion or the complement thereof with oligonucleotides comprising a nucleic acid sequence that is complementary to the bisulfite converted IRF4 DNA subregion under selective hybridization conditions, and measuring the methylation status of one or more cytosines in the DNA subregion, and assessing a second methylation status of DNA present in a second biological sample obtained from the individual at a second time point subsequent to the first time point, comprising: measuring a second methylation level status of an IKZF1 DNA subregion that is SEQ ID NO: 3 or SEQ ID NO: 4 or the complement thereof, by performing a bisulfite conversion of the DNA subregion and measuring the methylation status of one or more cytosines in the DNA subregion; and measuring a second methylation level status of a IRF4 DNA subregion that is SEQ ID NO: 5 or the complement thereof, by performing a bisulfite conversion of the DNA subregion and measuring the methylation status of one or more cytosines in the DNA subregion.

18. A method of assessing the methylation status of DNA present in a biological sample obtained from a human individual at risk of developing or of recurrence of, or suffering from, a large intestine neoplasm, consisting of: assessing the methylation status of an IKZF1 gene by measuring the methylation status of one or more DNA subregions located within the IKZF1 gene, wherein the subregions are SEQ ID NO: 3 or SEQ ID NO: 4 or the complements thereof, by performing a bisulfite conversion of the one or more DNA subregions, amplifying the bisulfite converted IKZF1 DNA subregions or the complement thereof with at least one oligonucleotide comprising a nucleic acid sequence that is complementary to a sequence that originates within the bisulfite converted IKZF1 DNA subregions under selective hybridization conditions, and detecting the methylation status of one or more cytosines in the one or more DNA subregions; and assessing the methylation status of a IRF4 gene by measuring the methylation status of one or more DNA subregions located within the IRF4 gene, wherein the subregions are SEQ ID NO: 5 or the complements thereof, by performing a bisulfite conversion of the one or more DNA subregions, amplifying the bisulfite converted IRF4 DNA subregions or the complement thereof with at least one oligonucleotide comprising a nucleic acid sequence that is complementary to a sequence that originates within the bisulfite converted IRF4 DNA subregions under selective hybridization conditions, and measuring the methylation status of one or more cytosines in the one or more DNA subregions.

19. A method of sequencing DNA present in a biological sample comprising: (a) sequencing one or more IKZF1 DNA subregions within the IKZF1 gene in a biological sample, wherein the IKZF1 DNA subregions are SEQ ID NO: 3 or SEQ ID NO: 4 or the complements thereof, by: performing a bisulfite conversion of at least a portion of the IKZF1 gene comprising the one or more IKZF1 DNA subregions, amplifying the bisulfite converted portion of the IKZF1 gene comprising the one or more IKZF1 DNA subregions or the complement thereof with at least one oligonucleotide comprising a nucleic acid sequence that is complementary to a region of the bisulfite converted portion of the IKZF1 gene comprising the one or more IKZF1 DNA subregions under selective hybridization conditions, and sequencing the bisulfite converted portion of the IKZF1 gene comprising the one or more IKZF1 DNA subregions; and (b) sequencing a IRF4 DNA subregion within the IRF4 gene in said biological sample, wherein the IRF4 DNA subregion is SEQ ID NO: 5 or the complement thereof, by: performing a bisulfite conversion of at least a portion of the IRF4 gene comprising the IRF4 DNA subregion, amplifying the bisulfite converted portion of the IRF4 gene comprising the IRF4 DNA subregion or the complement thereof with at least one oligonucleotide comprising a nucleic acid sequence that is complementary to a region of the bisulfite converted portion of the IRF4 gene comprising the IRF4 DNA subregion under selective hybridization conditions, and sequencing the bisulfite converted portion of the IRF4 gene comprising the IRF4 DNA subregion.