CN1861803A - 组胺n-甲基转移酶基因与原发性高血压的相关性 - Google Patents
组胺n-甲基转移酶基因与原发性高血压的相关性 Download PDFInfo
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Abstract
本发明公开了一种检测原发性高血压易感性的方法,它包括检测个体的组胺N-甲基转移酶基因HNMT的基因组序列,并与正常对照相比是否存在变异,存在变异就表明该个体患原发性高血压的可能性大于正常人群。其中,所述的变异是HNMT的单核苷酸多态性(SNP)及其组成的单倍型(haplotype)。本发明还公开了相应的检测试剂盒。
Description
技术领域
本发明涉及分子生物学和医学领域。更具体地涉及人组胺N-甲基转移酶基因(histamine N-methyltransferase,HNMT)的单核苷酸多态性(singlenucleotide polymorphism,SNP)及其组成的单倍型(haplotype)与原发性高血压的相关性。本发明还涉及检测这些SNP和单倍型的方法和试剂盒。
背景技术
原发性高血压(essential hypertension,EH)是最常见的心血管疾病,其发病率逐年上升,并可引起严重的心、脑、肾并发症,是脑卒中和冠心病的主要危险因素。EH是一种由遗传因素和环境因素相互作用而发病的多基因病,寻找EH相关基因进而阐明高血压发病的遗传机制已经成为目前研究的热点(HarrapSB.Hypertension:genes versus environment.Lancet,1994,344:169-171)。
定位克隆法是研究EH遗传机制的主要研究之一,即利用一定数量的覆盖整个基因组的微卫星引物,对大样本家系或同胞对进行连锁分析,而将EH易感基因位点定位到某一染色体区域。上海市高血压研究所已完成对上海地区汉族高血压家系的全基因扫描,研究提示2q14-q23区域与高血压存在紧密连锁关系(Zhu DL,Wang HY,Xiong MM,et al.Linkage of hypertension to chromosome2q14-q23 in Chinese families.J Hypertens 2001;19:55-61),然而并没有确定该区域内的众多基因中哪个基因为EH易感基因。
HNMT基因是一种定位于该区域内的基因,但目前没有证实HNMT基因与原发性高血压相关性的报道,更没有证实HNMT基因的SNP与原发性高血压相关性的报道。
综上所述,为了尽早治疗高血压,本领域迫切需要寻找原发性高血压易感基因,并开发检测原发性高血压的方法、试剂盒,以及相关的治疗药物。
发明内容
本发明的目的就是提供一种辅助性诊断(尤其是早期诊断)原发性高血压等高血压的方法及检测试剂盒。
本发明的另一目的是提供一种新的治疗高血压的方法。
在本发明的第一方面,提供了一种体外对个体的高血压易感性进行辅助性诊断的方法,它包括步骤:
检测该个体的HNMT基因的基因组序列并与正常的HNMT基因的基因组序列相比较,
存在差异就表明该个体患高血压的可能性高于正常人群,
其中所述的差异是在HNMT的基因组序列的第616、7798、40000、51951、和52109位,存在选自下组的单倍型:
(i)TAGAA
(ii)TGAGT,
其中,核苷酸位置编号基于SEQ ID NO:1。
在另一优选例中,检测的HNMT基因组序列来自于个体细胞的DNA抽提物。
在另一优选例中,所述的细胞是外周血白细胞。
在本发明的第二方面,提供了一种检测样品是否存在HNMT基因的单倍型的方法,包括步骤:
(a)用HNMT基因特异性引物扩增样品的HNMT基因,得到扩增产物;和
(b)检测扩增产物中对应于HNMT的基因组序列的第616、7798、40000、51951、和52109位的核苷酸,并判断是否存在选自下组的单倍型:
(i)TAGAA;
(ii)TGAGT;
(iii)TGAAA;
(iv)CAAAA
其中,核苷酸位置编号基于SEQ ID NO:1。
在另一优选例中,所述的单倍型是(i)TAGAA;或(ii)TGAGT。
在本发明的第三方面,提供了一种用于辅助性检测高血压的试剂盒,它包括特异性扩增HNMT基因的引物和说明书,所述的引物所扩增出的扩增产物含有对应于HNMT的基因组序列的第616、7798、40000、51951、和52109位的核苷酸,其中,核苷酸位置编号基于SEQ ID NO:1。
在另一优选例中,它还含有与第616、7798、40000、51951、和52109位的部位结合的探针。
在本发明的第四方面,提供了一种组胺N-甲基转移酶的cDNA序列或基因组序列的用途,它们被用于制备检测原发性高血压的试剂。
具体实施方式
本发明人经过多年研究,首次发现和证明了HNMT基因与高血压密切相关,而且发现了它的新功能:HNMT的改变将导致高血压,其中关联研究结果显示,在HNMT第616位的SNP01(C/T)、第7798位的SNP05(A/G)、第40000位的SNP07(A/G)、第51951位的SNP08(A/G)和第52109位的SNP09(A/T)组成的单倍型在病例和对照组中的分布存在显著性差异。基于此发现,本发明提供了利用检测HNMT基因或转录本是否存在所述单倍型,从而为诊断高血压提供辅助性或早期参考指标的方法和试剂盒。
HNMT基因的总长度为52427bp,其详细序列可参见网址http://genome.ucsc.edu/或http://www.ncbi.nlm.nih.gov/或参见SEQ IDNO:1。
基于本发明的新发现,HNMT蛋白或多肽有多方面的新用途。这些用途包括(但不限于):直接做为药物治疗HNMT蛋白功能低下或丧失所致的疾病(如高血压),和用于筛选促进HNMT蛋白功能的物质,如抗体、多肽或其它配体。用表达的重组人HNMT蛋白筛选多肽库可用于寻找有治疗价值的能刺激人HNMT蛋白功能的多肽分子。
另一方面,本发明还包括对人HNMT DNA或是其片段编码的多肽具有特异性的多克隆抗体和单克隆抗体,尤其是单克隆抗体。这里,“特异性”是指抗体能结合于人HNMT基因产物或片段。较佳地,指那些能与人HNMT基因产物或片段结合但不识别和结合于其它非相关抗原分子的抗体。本发明中抗体包括那些能够结合并抑制人HNMT蛋白的分子,也包括那些并不影响人HNMT蛋白功能的抗体。
本发明不仅包括完整的单克隆或多克隆抗体,而且还包括具有免疫活性的抗体片段,如Fab’或(Fab)2片段;抗体重链;抗体轻链;遗传工程改造的单链Fv分子;或嵌合抗体。
本发明的抗体可以通过本领域内技术人员已知的各种技术进行制备。例如,纯化的人HNMT基因产物或者其具有抗原性的片段,可被施用于动物以诱导多克隆抗体的产生。与之相似的,表达人HNMT蛋白或其具有抗原性的片段的细胞可用来免疫动物来生产抗体。多种佐剂可用于增强免疫反应,包括但不限于弗氏佐剂等。
本发明的抗体也可以是单克隆抗体。此类单克隆抗体可以利用杂交瘤技术来制备。本发明的抗体包括能阻断人HNMT蛋白功能的抗体以及不影响人HNMT蛋白功能的抗体。本发明的各类抗体可以利用人HNMT基因产物的片段或功能区,通过常规免疫技术获得。这些片段或功能区可以利用重组方法制备或利用多肽合成仪合成。与人HNMT基因产物的未修饰形式结合的抗体可以用原核细胞(例如E.Coli)中生产的基因产物来免疫动物而产生;与翻译后修饰形式结合的抗体(如糖基化或磷酸化的蛋白或多肽),可以用真核细胞(例如酵母或昆虫细胞)中产生的基因产物来免疫动物而获得。
抗人HNMT蛋白的抗体可用于免疫组织化学技术中,检测活检标本中的人HNMT蛋白。一种优选的抗HNMT抗体是不识别正常HNMT但识别突变HNMT的抗体,或者识别正常HNMT但不识别突变HNMT的抗体。利用该抗体对正常和异常HNMT蛋白的特异性差异,可以方便地进行蛋白质水平的高血压易感性检测。
利用本发明HNMT蛋白,通过各种常规筛选方法,可筛选出与HNMT蛋白发生相互作用的物质,如抑制剂、激动剂或拮抗剂等。
本发明HNMT蛋白及其抗体、抑制剂、激动剂、拮抗剂等,当在治疗上进行施用(给药)时,可提供不同的效果。通常,可将这些物质配制于无毒的、惰性的和药学上可接受的水性载体介质中,其中pH通常约为5-8,较佳地pH约为6-8,尽管pH值可随被配制物质的性质以及待治疗的病症而有所变化。配制好的药物组合物可以通过常规途径进行给药,其中包括(但并不限于):肌内、静脉内、或皮下给药。
正常的HNMT多肽有望用于疾病治疗,例如,用于高血压治疗。在使用本发明HNMT蛋白时,还可同时使用其他治疗高血压的药剂。
本发明还提供了一种药物组合物,它含有安全有效量的本发明HNMT蛋白以及药学上可接受的载体或赋形剂。这类载体包括(但并不限于):盐水、缓冲液、葡萄糖、水、甘油、乙醇、及其组合。药物制剂应与给药方式相匹配。本发明的药物组合物可以被制成针剂形式,例如用生理盐水或含有葡萄糖和其他辅剂的水溶液通过常规方法进行制备。诸如片剂和胶囊之类的药物组合物,可通过常规方法进行制备。药物组合物如针剂、溶液、片剂和胶囊宜在无菌条件下制造。活性成分的给药量是治疗有效量,例如每天约0.1微克/千克体重-约10毫克/千克体重。此外,本发明的多肽还可与其他治疗剂一起使用。
使用药物组合物时,是将安全有效量的HNMT蛋白或其拮抗剂、激动剂施用于哺乳动物,其中该安全有效量通常至少约0.1微克/千克体重,而且在大多数情况下不超过约10毫克/千克体重,较佳地该剂量是约0.1微克/千克体重-约100微克/千克体重。当然,具体剂量还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。
人HNMT蛋白的多聚核苷酸也可用于多种治疗目的。基因治疗技术可用于治疗由于HNMT蛋白的无表达或异常/无活性的HNMT蛋白的表达所致的细胞增殖、发育或代谢异常。构建携带HNMT基因的重组病毒载体的方法可见于已有文献(Sambrook,et al.)。另外重组人HNMT基因可包装到脂质体中,然后再转移至细胞内。
检测HNMT基因的突变也可用于诊断高血压。检测可以针对cDNA,也可针对基因组DNA。HNMT蛋白突变的形式包括与正常野生型HNMT DNA序列相比的点突变、易位、缺失、重组和其它任何异常等。一类优选的突变是由SNP构成的单倍型。可用已有的技术如Southern印迹法、DNA序列分析、PCR和原位杂交检测突变。
本发明的主要优点在于:
首次用实验证实了HNMT的改变与高血压的密切相关性,进而提供了辅助性诊断高血压(或易感性)的方法和试剂盒。本发明可以为临床诊断(尤其是早期诊断)高血压提供极为有价值的辅助性参考指标,从而有利于实现早诊断、早预防、早得益。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件如Sambrook等人,分子克隆:实验室手册(New York:Cold Spring Harbor Laboratory Press,1989)中所述的条件,或按照制造厂商所建议的条件。
实施例1
1对象与方法
1.1研究对象
1.1.1中国人SNP发现和确认样本
样本为来自24个核心汉族高血压家系、无亲缘关系的24例原发性高血压病人。
1.1.2SNP分型和关联分析研究样本
所有受试者均为汉族。原发性高血压组(EH组)和正常血压组(NT组)各96例,均来自中国上海地区,彼此无亲缘关系。EH组为上海市瑞金医院高血压科住院病人,均为汉族,无亲缘关系。平均年龄为57.32±11.75岁。入选标准:
收缩压140mmHg和/或舒张压90mmHg,或正在接受抗高血压药物治疗至少一年以上;
在30岁之前或60岁以后发病者除外;
临床上除外继发性高血压,如原发性醛固酮增多症、嗜铬细胞瘤、肾性高血压等。
NT组为上海地区40岁以上居民,均为汉族,无亲缘关系。平均年龄56.39±6.45岁。收缩压<140mmHg且舒张压<90mmHg,无服用抗高血压药物史,排除肝、肾功能障碍、甲状腺疾病、糖尿病、冠心病史。
1.2实验方法
1.2.1DNA提取
常规酚-氯仿法提取外周血白细胞DNA,并标化DNA浓度值至20ng/μl。
1.2.2PCR及测序引物的设计
根据GenBank中HNMT的基因组序列,应用prime3软件(美国麻省理工生物医学白头研究所,http://www-gonome.wi.mit.edu/cgi-bin/primer/primer3_www.cgi)设计引物。具体引物如下表所示。
表1 引物序列表
引物名称 | 位置 | 序列(5’-3’) | SEQ ID NO: |
HNMTP1 | 上游 | atatttgacagcaggcaagg | 2 |
下游 | ccgggggaaagtgtaatatc | 3 | |
HNMTP2 | 上游 | gtttcagccaaagtcagaca | 4 |
下游 | ctgccctctaagcattcaaa | 5 | |
HNMTP3 | 上游 | aggttgcagtgagtggagat | 6 |
下游 | gaagctgcatttaggggaat | 7 | |
HNMTP4 | 上游 | tgcacttttaccctggtgtc | 8 |
下游 | gcaaggctgtaaatccactg | 9 | |
HNMTE1 | 上游 | tgcaaagtcccgttcaaata | 10 |
下游 | taattcgcccttatccctgt | 11 | |
HNMTE2 | 上游 | actgccatttccaagtctcc | 12 |
下游 | cgatctcttccaaaagcaaa | 13 | |
HNMTE3 | 上游 | agggcagcagttgaacatta | 14 |
下游 | gtttagtcatgcctgccaag | 15 | |
HNMTE4 | 上游 | tctggtctcccagacataaga | 16 |
下游 | ggcagatcatggtcacttgt | 17 | |
HNMTE5 | 上游 | tgctatggaagccagaaaga | 18 |
下游 | gccaaggcaagaatttcata | 19 | |
HNMTE6-1 | 上游 | tatgagctgcacaaaggaca | 20 |
下游 | ccttcccctctttcttagca | 21 | |
HNMTE6-2 | 上游 | actttaatgccacagcacca | 22 |
下游 | tcagacaatcagcaaatgga | 23 |
1.2.3HNMT基因的调控区和编码区分段体外扩增
以提取的DNA为模板,用Taq酶,在GeneAmp 9700 PCR仪上以Touchdown程序进行PCR扩增。反应条件为:94℃预变性2分钟,94℃变性30秒,63℃退火40秒,72℃延伸40秒,共10个循环,每个循环退火温度递减0.5℃;以后94℃变性30秒,58℃退火40秒,72℃延伸40秒,共30个循环;最后72℃延伸7分钟。PCR扩增产物经琼脂糖凝胶电泳验证。
1.2.4SNP的发现和检测
PCR产物经Resin树脂纯化后,用ABI-PRISMTM 377 DNA测序仪(美国应用生物系统公司appliedbiosystems(ABI))进行荧光标记末端终止法双向测序,用Polyphred软件(美国华盛顿大学http://droog.mbt.washington.edu/Polyphred.html)进行序列的判读和SNP确认。
1.2.5SNP基因分型和关联分析
用直接单向测序法进行SNP基因分型,即在96个高血压病人和96个正常血压对照组中进行分型和关联分析。
1.3统计学方法
SNPs各基因型在病人和正常血压对照中分布的比较采用R×C表χ2检验。P<0.05认为有统计学差别。
2.结果
2.1HNMT基因SNP的发现和分布
HNMT的基因共有6个外显子,测序总长度是4926bp(其中启动子区为1959bp,5′UTR为252bp,编码区为879bp,内含子为1525bp),共发现9个SNP,包括启动子区4个,编码区1个,内含子2个,3′UTR2个。其中SNP02,SNP04,SNP05,SNP06,SNP08,SNP09都是首次发现的SNP。HNMT基因SNP分布情况见表2。
表2 中国人HNMT基因SNP的种类及其分布
SNP名称 | 在基因序列中的位置 | 基因区域 | 等位基因 | 检测引物 |
SNP01 | 616 | Promoter | C/T | HNMTP1 |
SNP02 | 1458 | Promoter | C/T | HNMTP2 |
SNP03 | 1790 | Promoter | C/T | HNMTP4 |
SNP04 | 1841 | Promoter | C/T | HNMTP4 |
SNP05 | 7798 | intron | A/G | HNMTE1 |
SNP06 | 39840 | Exon | C/T | HNMTE4 |
SNP07 | 40000 | intron | A/G | HNMTE4 |
SNP08 | 51951 | 3’UTR | A/G | HNMTE6-2 |
SNP09 | 52109 | 3’UTR | A/T | HNMTE6-2 |
说明:
(1)表中第一列为SNP的名称;第二列为SNP在HNMT基因序列中的位置;第三列为SNP所属基因区域,Promoter为启动子区,Exon为外显子区,Intron为内含子区,3′UTR为3′末端非翻译序列;第四列为在等位基因中SNP的两个碱基;第五列为测序所用引物。
(2)SNP02,SNP04,SNP05,SNP06,SNP08,SNP09为新发现的SNP。
2.2SNP位点的基因分型
在96例EH和96例NT中,对SNP01、SNP05、SNP07、SNP08和SNP09进行基因分型、关联分析和单倍型分析。
关联分析结果提示,各SNP等位基因分布在两组中无显著差异(P均>0.05)。
5个SNP位点,单倍型分析估计得9种单倍型(频率均>1%),解释96.74%的EH和94.51%的NT个体,单倍型分布在EH组和NT组间存在显著差异(见表3)。其中,EH组TAGAA和TGAGT单倍型频率显著高于NT组,TGAAA和CAAAA单倍型频率显著低于NT组(P均<0.05)。
具体地,对于TAGAA而言,在EH和NT的出现频率之比为0.2011∶0.0659(约3∶1),故每4个具有该单倍型的个体中有3个是高血压患者(或尚未患病的高血压易感者)。
具体地,对于TGAGT而言,在EH和NT的出现频率之比为0.0598∶0.0165(约3.6∶1),故每4.6个具有该单倍型的个体中有3.6个是高血压患者(或尚未患病的高血压易感者)。
具体地,对于TGAAA和CAAAA而言,具有该单倍型的个体中大多数不高血压患者,也不易患高血压。
表3 HNMT基因单倍型在EH组和NT组分布比较
单倍型 | EH组(n=96) | NT组(n=96) | X2 | P | ||||||
SNP01 | SNP05 | SNP06 | SNP08 | SNP09 | 频率 | 染色体数 | 频率 | 染色体数 | ||
TTCCTTCCT | GAAAGGAAA | AGGGGAAAG | AAAGAGGAG | AAATATTAT | 0.27720.20110.16850.10870.07610.05980.03800.02170.0163 | 533932211511743 | 0.40660.06590.08240.14290.10440.01650.03300.08240.0110 | 781320162036162 | 7.2415.043.200.750.794.740.087.600.21 | 0.0070.0001>0.05>0.05>0.050.029>0.050.006>0.05 |
EH,原发性高血压NT,正常血压对照
3.讨论
高血压是遗传因素与多种环境因素相互作用而导致的多基因疾病,其遗传机制的研究已经成为目前的研究热点。迄今研究者已经成功地确定了几种单基因遗传性高血压的候选基因,但占高血压约95%的原发性高血压的遗传方式和易感基因仍未确认。定位克隆法是研究EH遗传机制的主要研究之一,上海市高血压研究所已完成对上海地区汉族高血压家系的全基因扫描,研究提示2q14-q23区域与高血压存在紧密连锁关系,HNMT即为该定位区域内的众多候选基因之一。
由于多基因疾病表现型的复杂性、相关基因的微效性和人群的遗传异质性,其相关基因定位克隆研究一直是一个很大的挑战。在原发性高血压候选基因中筛选多态性标记,然后在病例-对照中进行相关分析是目前寻找疾病相关基因的重要方法之一。SNP数量多、分布广、密度高,是进行遗传连锁分析和关联研究最理想的遗传标记。
人的HNMT基因位于2号染色体上(2q22.1),编码组胺甲基转移酶,有6个外显子,广泛表达于肝、肾、肺、脾等组织(Aksoy S,Raftogianis R,Weinshilboum R.Human histamine N-methyltransferase gene:structuralcharacterization and chromosomal location.Biochem Biophys Res Commun 1996;219(2):548-54)。已发现该基因变异可能减少组胺的代谢,进而导致支气管收缩。由于组胺的扩血管作用,这个能够调节组胺降解的基因可能与高血压有一定关系。
本发明首次对中国汉族人群进行了HNMT基因的SNP检测,发现了位于启动子区的4个SNP、编码区的1个SNP、内含子区的2个SNP和3′UTR区的2个SNP。其中6个SNP尚未被收录于NCBI的SNP数据库(http://www.ncbi.nlm.nih.gov/SNP)中。本发明对其中的5个SNP在各为96例的高血压病例和正常对照人群中进行了基因分型,虽然没有发现单个位点的等位基因频率和基因型在两组之间有统计学差异,但发现4种单倍型分布在EH组和NT组间存在显著差异,EH组中TAGAA和TGAGT单倍型频率升高,NT组中TGAAA和CAAAA单倍型频率升高。基于这些发现,可以开发辅助性诊断(尤其是早期辅助性诊断)原发性高血压的试剂和试剂盒。
实施例2
原发性高血压易感性检测试剂盒
制备一试剂盒,它含有:
名称 | 序列(5’→3’) | SEQ ID NO: | 浓度 |
HNMTP1正向引物 | atatttgacagcaggcaagg | 2 | 干粉20D |
反向引物 | ccgggggaaagtgtaatatc | 3 | 干粉20D |
HNMTE1正向引物 | tgcaaagtcccgttcaaata | 10 | 干粉20D |
反向引物 | taattcgcccttatccctgt | 11 | 干粉20D |
HNMTE4正向引物 | tctggtctcccagacataaga | 16 | 干粉20D |
反向引物 | ggcagatcatggtcacttgt | 17 | 干粉20D |
HNMTE6-2正向引物 | actttaatgccacagcacca | 22 | 干粉20D |
反向引物 | tcagacaatcagcaaatgga | 23 | 干粉20D |
PCR反应液 | 含Taq酶dNTP镁离子PCR反应缓冲液 |
抽取待检测高血压病人的血液3ml,使用常规方法(或使用特定的试剂盒)从血液中提取DNA。将高血压检测试剂盒中的PCR引物稀释到1μmol/μl,以所提取的DNA为模板与所提供的引物进行PCR反应。PCR产物纯化后,用ABI-PRISMTM 377 DNA测序仪进行荧光标记末端终止法双向测序,用Polyphred软件进行序列的判读和SNP确认。
用本实施例的试剂盒对近百例待测对象进行了检测,发现26位具有(i)TAGAA或(ii)TGAGT单倍型的个体,再对其进行血压测量,结果证实其中19位的血压高于正常人。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
序列表
<110>上海市高血压研究所
国家人类基因组南方研究中心
<120>组胺N-甲基转移酶基因与原发性高血压的相关性
<130>055215
<160>23
<170>PatentIn version 3.1
<210>1
<211>52427
<212>DNA
<213>智人(Homo sapiens)
<400>1
tcctcactgg gatccacatg aagaactggc tctgttggag aatatttgac agcaggcaag 60
ggaggtgatg gtctcagaag accaagtttc agttaaggga ggccttaaca gcagctttcc 120
aagagaaagt catgtcagga gtattcctca gcagaatagc aaacagagac tcttactaaa 180
cttttattca atagatgaat acattattgg ccatttttgg ttttggttaa agtgaaacaa 240
aaacagatag atgttacaca tgaatgaatg aatgatttgg gttgagctct aaagagaaaa 300
atggaagatg gtaatagaag caaaagtttg tcagagccca tctgaggaaa gggaaggctg 360
gttggataga gatgtgagta aagaaccagc aaagacctta tctaaggatg agtgaagggc 420
acaggagcta aatcagggct tggccaaata aggcctgtgg ccaaacccaa ccctaccaac 480
ctgatttgtg cagcccatga gctaccaata acttttatgt ttttatatgg ttaaagtaaa 540
ttcaaagaag gataatattt catgacatgt gaaaatgata tgaaactcaa atttcaatgt 600
ccgtgaataa agtgacgact gtttttgtca ttttatatat atatattttt tttgcagagg 660
gactggcttg cactttttaa acattagtta tattattctc agtacaaccc tataagataa 720
aattcattcc cattttactg atgagcaaac tgcagcttat gtttcagcca aagtcagaca 780
gttcattaag ggcagagtca tccatggcaa tctgcctgtc cagatattac actttccccc 840
ggggtaaaag cactggctct aagaatagtg agaacaaaac atacttataa aagggagttg 900
ggggctggga atggtggctc acgcctgtaa tcccagcact ttgggaggcc gaggcgggtg 960
gatcacttga gatcaggagt tcgagatcag cctggccaac atggtgaaac cctgtctcta 1020
ctaaaagtac aaaaattagc caggcgtggt ggcgggtgcc tgtaatccca gttattcggg 1080
aggctaagac aggagaatca cttgagtcca ggaagcggag gttgcagtga gtggagatcg 1140
caccattgca ctccaggctg ggcgacagag cgatactctg tctcaaaaaa aaaaagagag 1200
ttgggaagtg ttttgaatgc ttagagggca gcttgggaac tcaattagaa gaagggacgg 1260
tttaagcaga catatttcta agagacttat atgagttaac tcatttgatc ctcagcactc 1320
ctccatgagt tggatgctat tattaacaac ccaatattag ataaaggatg accttcttaa 1380
agacctcttc ccaggaaaaa gactgtgtgt gggtactctg aagctttggc tcttctggtg 1440
gggacaccac tgggtttcca aaggctcatc cagccaagcg aagtatctat gacctcgtcg 1500
tgttcagcgc gcttagggaa ggattctatg gactgcactt ttaccctggt gtcctgcatt 1560
cttgctccaa gacttctctt accactctca ttcccctaaa tgcagcttct gacaccttct 1620
agctacgagt tcttgggctc ctccttcgtg acttcctttt aagataattt ctgagttaca 1680
acaaatcagc atttgaagaa atgcagcaga taagttgaaa attcaagtgc tgaggaatgt 1740
aaaggcccaa aacaatcccg tagaaagcac agaggcagat gacagtcttc gttaaagatt 1800
tcactgctgt agatttctga gagtgctgtg tagctgtcct cttatcctgg tgtttgccac 1860
ttcgaacagt cactttccca cttggaactt acttgtggct ttgctgacaa aacaggaagt 1920
gatttgaata cagtttgttt ttatgacctt tcaacctcag gaatttgaaa agttttagca 1980
gtggatttac agccttgctt aatacttcta tttcttacaa aacaaccgta taggggttaa 2040
agtatcagtg caaagtcccg ttcaaatatt gactcagtaa tgagctctac aagccagcct 2100
ttgtggcatg ttaaattcaa aacaagctta gcattttttt tttttttttt ggatagaaac 2160
tggtgggggt ggggaaagaa agagggaact gggaagagaa ggaggggaac ttaaaccttg 2220
cttcctgctc tgtctttctc agaaaaccaa atatggcatc ttccatgagg agcttgtttt 2280
ctgaccacgg gaaatatgtt gaatctttcc ggaggtttct caaccattcc acggaacacc 2340
agtgcatgca ggaattcatg gacaagaagc tgccaggcat aataggaagg taacaaaagg 2400
gacgttgttg tcaaagggac aagcctcaga ctggctgtgc gtcagtgata gatgggtctc 2460
gctcagcctc gcaggctggg cacagggata agggcgaatt actgatagca gctccccgtc 2520
gtcccctcct cgctgccctg ccctgccttt ctcctgcagt gctttggttc cacgtttgct 2580
ttgaacactc aaaggctccc atttgtgttg tatttccagc tgcatagaga taagcgttaa 2640
ccatttgaag gcacaaatcc atgttcattt gggaaaagat aagatgctaa tcttcgaact 2700
cagatttttc agccctcctc caaattttac atcccaaaaa agtcccaaag ggagtctggt 2760
atgcttttca ttagaatcaa atataaataa ttgccaaagt acgatttgcc ctgaggattg 2820
agtgcctcag ttctcataat atccatttaa attaattttc cttatccatt gttatagtta 2880
tcactctctt cctcaaaatt gtctttttct ttcagcttaa tattagcaat gtgttcctta 2940
aaaaaagaac cattttccca ttatcagtga aactcactgg ttcctatcct tcttgcagag 3000
ttcttttttt tgggtgatta atgtgttcaa tttgtgccag agctgataag cattatgaga 3060
gtaacagatt ccacatgcta aagataatca aatcacctat ctgggggtga tttgctgtaa 3120
ctcattctac ttcaggaaat aataatggaa aactgggaag aaatgactat ggatccaatt 3180
tgcaaacagc aaaggaaagt ggtattttat cttttgctga atttctctat tgcaggcctg 3240
aaattctttc accagggcag tacctatgtc tgaccagagc aggcattatt agatgtacat 3300
aaaattttat ttccttttct atttaacatg attcagattt taaatgttag ctttcaaaaa 3360
ataggatatt atatattaaa aattaatatg taataggata aggatgcaaa catcaaagca 3420
aatagcaaat atagagaact tcttacctag gaactaatta tagttaacct ctttgggttt 3480
ctttgctcat ttctaaagtt aaaggtaatg agttaatttc tcaattcttt ttcagtacta 3540
aaagtatttg ctcatgtctg tagcttacca gatccttggt tttcttcagc catacacagt 3600
ttggtttgaa gaggtaccgt ggatggagat aacataatcg atgatgaatg accccttcct 3660
tatcttcaaa gtttaaatct aactggaaat attataaaat ctgtgaaaga ctgaagaatt 3720
tttaagggca cactgtttgt cttataacag tagtatatag ttaggaatga tcagattcag 3780
tgtcatttat ttttttcctg aaggtaatgt ttgaaataag atttagctga aggactttta 3840
aaattgttac ttagagttgt ctataagtta tgaagtacca aaatgtgatt aggatactct 3900
ttgtgtatgt tagggcaggg tttgttgagt ttgtggctca ctgtgctaat tgagtgtgga 3960
gcgagcctat taaattttta ttaaagcaag acatgccata ttttaaaaca tcaaatggtt 4020
ctaaagtgtg tggggactat aacaaacccc acccactcca ttcttgattc ccactctccg 4080
gaagcaacca ctttcagcac tttgaaatct tttagttatt tatggaattt tctttcataa 4140
ttcaaaataa catgttattg ttctatttct tcatttcgct gtattaaaat agctaagtaa 4200
gcatgcatat ttcccaccct atcatgtcac tatatgtagt caaaattttg gttaaataat 4260
ttgagtgttt atgttatttt gcctatgtac atattcttaa taattgagca atatattcga 4320
ctatgcttat atttcctttt acgtacaact ttttgttctc cctagagttg actattgcct 4380
tgattttggt ttcttttctt agttctccat gtacctatta ctattttgat ccccaagcag 4440
atatattaat ctcctctcaa tatatgcaaa catatcaagg aatctgttta ttttacccca 4500
agggaacaac ttttctgaag ccctctgttc tttttttcag tttaggaaga tctgctttgg 4560
cctgctatac aactattaag gagggaattt atttcacttt ctgagaatca ttttctttct 4620
ccattatttg attccctgat tctatatctc atgcctttct tttctttgtt tcctcggtcc 4680
tttgtttcct gaacaattct ttaagaactt taagagtgaa cgagaggtaa actttttgag 4740
actttgtatg tttaaaaatc ccttggttct atgttaatcg tttgactgga tatagaactc 4800
tatactgaaa atggttttgt ataatagatc taaaggtact tttccactgt cttttagata 4860
ccagaattgc tgttaacaaa taaaatactg gccagatgtg ttggttcacg cctgtaatcc 4920
tagcacttcg ggaggctgag gcgggaggat tacttgagcc taggagtttg agaccagcct 4980
gggcaacata gcaagatccc atctctacaa aaaagtgaaa aagttagctg aacaaggcgg 5040
catgcacatg ctactccaga cgctgaagtg ggaagatcac ttaagtccga gagatcgagg 5100
cttcagtgag atatggctga gacactgctc tcagcctgga tgacagagtg agaacctgtc 5160
tcaaacaaga gaaaaaaata aatcaaatgc tactcaaaat tctcatcctt ggcatgtgga 5220
ataactttta cattgctatg tgttttgttt tccctatttt gaacttttta gaatcttctt 5280
acgtctagta ttctgaaatt ttaaaatact gagctgtgaa atggttcctt tttacccatt 5340
ttatgggtac tccctgggct atttcaattg agattcagat ccttcagtta tgcggaactt 5400
tggtaatcat tcttcaccac tgttttcttt ttctggaact tttattcatc aaatacttcc 5460
tggattgatt acctaatttt cttatatttc cagtttgcta caactttcct ctttcagccc 5520
atgtattaac tttttactat tatattttta atttccaaga atgttttcta tagcattctt 5580
ttcatcattc ccagatgtaa taccttctta ttcattacaa aatgttcctc tgctctctct 5640
gcctctttcc atctctgttt cttatgttag acagctcccc aaccacctaa agagccttgg 5700
ttttctattc aatcaaataa tgaggcacta aaaggtagtc agattctctt tgtgtaagtc 5760
agggcagggt ttgttgagtg agtagctcac tgaataattg agtgtggact cagctctttc 5820
ctgggagatc ctcagatata aaatcatgtt aactttatca ctgagatgat ttgtttccct 5880
atagaggaat tcttcaatcc cctatttgag ggtagatggt ggggcagggc ttgggggcag 5940
gaaaaattat agtaaataac tataaatagt aaagttggtt attgttgttg catataaaac 6000
atttaaatcc ttggctagaa aatagtaagt tttcaataat tatttgatgt cattataata 6060
tgtgaaatgg gatgaataat agtatctaac tcatagagga atttcaagga ttcaaagagt 6120
taattcacat aaatcactta catgtaccta gaatcataat aattgctaat atatgtggag 6180
tgcttgtcat gtgcagatac atttctaaga gatttgcatg aattaaatca ttgaatcctc 6240
acaacttctc catgaattag aaacagttat taataatcct acaagagaga tgatattatt 6300
atcttatttc acagagatgt caaataactt gctcaaggta acataacagt aacctgggat 6360
ttcaacttgg gtgctctgct tcatagcctc cctatgctgt catagatgta agcattttaa 6420
agaatgaaca aaaggtgtag atagaaatgg atgtgttagg actcaggatt atgagttgga 6480
ggataattag aattgaagaa ggcaaatcat ttataggtgt tctcgaccct agactttgca 6540
agattccttt agaaccttac ttcaattttt gttcccatcc tgtgactgag caggcttttt 6600
gcactgtaga caaaacacag ttttgtttgc catcccaaag tccaaagaaa caaacaccat 6660
ccttttccct tcatggttct cctacagcag tcatctcttt tccttctctc tttcaccctg 6720
tttcaacaga ctctagatct gcttcctcat ttttgagctc agttttaatc ccattgccat 6780
ctgacttcag tcttcaatct tcttttacaa ctgccattac taaagacact cgtattgcca 6840
aattcgatgg agatttttcc ttttttaagt agtacactct gctgcttttg ccatgacgac 6900
gggctttctc tgcctccaat tactctggta cctctctgtg ctttatttct tttcttctct 6960
gtcttctttg tatattcttc acaatccagt gatctttaga agttggtatt gcatcaccat 7020
ccactactac tataactctg caatatcttt gggtgatgga atctactttt ctagcactga 7080
ccattacttt atgatgatga ttctccagaa tacatcattg accctgattt ctctcctccc 7140
agcttaaatc ttgcaaatcc aaatgtctgc tgaattcgta tttatttttt ttaaaagccc 7200
tgacaaaaca taagcttgct gccaaactgt atttctcagc ttcctttttg gcatcaccct 7260
ttgcccagtc atccaagcct gaaacaggga agtcactgtg cattcatatt tttttctgac 7320
ctcttcacat caatctaaca gcaagtccta ctggcttatt tcccaatctg tccactccac 7380
tctatttcta gtacctgagt cataattcgg gctttattat ctcacatttc attttgagag 7440
caaagtgata tctgtttttt taatgcctag gatagaatac acataatgca tgtttaataa 7500
acacttgttc attaaaagga aggttaaaaa aagggggagg aaagaaggca aacattatag 7560
atagtgggaa ccagctgagc ctttccttta tctacgatga gtggcttatt atatgactag 7620
actcaaaact ccactttttc tgttcttgtt ctccaagcca taaccaaaca aatggcattt 7680
tgtacctctg atatgtacat actgccattt ccaagtctcc cagttaaaga ttgttaatga 7740
ataaaaccta tattttgaaa tatactctaa agatggcaat ataactgata taattgggac 7800
atttcatgtt ggcctagttt tcattcattg tatttttagt ctgttctctt caactagact 7860
agataatcag atttcacaaa gcacctaaca catttttcta aaactacata atttttttct 7920
ttcaggattg gagacacaaa atcagaaatt aagattctaa gcataggcgg aggtgcaggt 7980
atgagtaata tatttttaaa gttcatattt cactttaacc attatgctgt gtgatgacaa 8040
tattgttcat tttttaggaa gacttttttt ttttgctttt ggaagagatc ggcttattaa 8100
aactagcaat attacttcaa ctaacattaa tgcccccata gatttacagg gtttaggaca 8160
ttagccttca ttactatctc tattgtgaat aagtgatgtg acttgttctt ttgatagatg 8220
aaaaatcaaa taggataact ttaaggataa ctcttatcca aaatgattaa aatactcaca 8280
gaaaaggaaa atctcataat aagcttctta agtttgtgcc atttaaaacc ttgttcatgg 8340
actggttact gttttcaaac tgttattggt ccatgtgaag atctgaaatg tgcacaggag 8400
gctgggcgcg gtggctcacg cctgtaatcc cagcactttg ggaggctgag gggggcggat 8460
cacgaggtca ggagatcgag accatcctgg ctaacgcggt gaaaccctgt ctctattaaa 8520
aatacaaaaa attagccaag cgtggtggca gacgcctgta gtcccagcta ctcgggaggc 8580
tgaggcagga gaatggcgtg aatcctggag gcggagcttg cagtgagccg agatcgcgcc 8640
actgcactcc agcctgggtg acagagcgag actacgtctc aaaaaaaaaa aaaaaaagaa 8700
agaaagaaag aaagaaagaa agaaagaaag aaaaaagaaa tgtgcactgg aatataaact 8760
gatgcacagc ttttttcatt gagaaagtct caccatgggg aaaaatgtgc tcagtgacag 8820
agttaattta cattcttgtg aactcattct ttgagtggca tgggcctaat ctgttccctt 8880
cctcttactc agttccaaaa ctgaatgctt agaattacct ctagcattca gataactcct 8940
aagcaccttt ttttttttga cggattctca ctctgtcgcc caggctgaaa tgtgcagtgg 9000
tgcaatcttg gctcactgca acctccacct cccgggttca agcaattctc ctccctcagc 9060
atcctgagta gctgggatta caggcaccaa ccaccgcacc tggctaattt ttgtattttt 9120
aatagagacg gggtttcacc atcttgtcca ggctggtctc aaactcctga ccttgtgatc 9180
cactcacctt ggcctcccaa agtgctggga ttacaggcat gagtcacatg cccagcccta 9240
agcatacttt tataggcatt ttatagtgtc attactttta gatccagtgc tttcattcta 9300
ggggaaaatt taaagtctgg aaaggtagat ggacacaggt aactcagcct ccagtgaaat 9360
ttatgatctt ggctaaaaca tcagtaaaat gggaacaatg aattttatct cataaggttg 9420
tagtgagagt gatataggta acatttacaa agtgcttagg acattcttat tgctcctgga 9480
gagtgaaggc tattcccttc tgcaaaagta aaataagttt catctcaaga cttttcctaa 9540
tatcaactcc tgaacagtgt ttgccttatt tttaagtcat ctggaagttt gggttaatgc 9600
attaatatat aaaatatgta gatatattat ttatatattt atctttagtt attttctttt 9660
gtctgagtga tagttcagta atggttacaa ctcgatatca agtggacact attgtcactt 9720
gtaacttaat gccaagtggt aatcccttga acctcttaag tataagtgtt ctagtgcccc 9780
atgaatgagt tgaactgtgg ctcatattaa cacaaagata actaagagct ctctaatgaa 9840
atgagatcac tgattttttg tttttgtttt ttgtttgttt tttgagatgg agtctcgctc 9900
tgttgcccag gctagagtac agtggcatga tcttggctca ctgcaacctc tgcctcctgg 9960
gttcaagcaa ttctccctgc ctcagtctcc cgagtagctg ggattacagg aaactgccac 10020
cacacccgtc taatttttgt attttttagt agagaagggt ttcaccatgt tggccaggct 10080
agtctcgaac tccttacctc aggtgatttg tctgcctcgg cctcccaaag tgctgagatt 10140
acaggcatga gccaccatgc ccgacagaga tcactaattg ttaatgtcat tatttgttaa 10200
tttttcatga aatacactgt gatatagtgt aataagaact aatcattaaa atcattttac 10260
tttattatca tctttcacca agaaaataga aaccaacaaa gacagacaat gaagggaatt 10320
gtcatgaaca ataccataga gggtatttaa gctaaaatac tttattattg gttatacttt 10380
aagtccccaa aattataata gttatgaatt gtctaaagaa tgtcttatta attcatttaa 10440
ccaagacagt tatttcctgt gtgttttgga tatgagtttc aggcaaccaa caggcaatga 10500
gactatcatt tgatagtgtc acttgtgctt ggacaagaag agaaggccta caagaaaaag 10560
taattaaaaa caatctctat catggccaag ttaattgacc ttttaatata aagttaattg 10620
aatttctaat gcaaatttat ccagatgctt ataagctatc tagagaaagg aacgtttggc 10680
ctgcacagtg agtccttaca taaaggtgca catggaagct aatacagaga acttaacaaa 10740
ataaagggaa caactcttgg agttcttctg actgagccct aataatgtat taataacaaa 10800
ctccaccttg gggagaatgt gggtgccctt taaggtcact tttcataaga aatcaatcag 10860
aaatgtaaga aaaactccaa gaaaaattta agttatatat acttagcttt cactacccaa 10920
ctaagttata tgaaatcaaa agcaatgcat ttaaaatccc taggtctagg tgtctgttgc 10980
ttgaaagaac agtgttttga ggggaaagga cactctactt cagttagttt gagtgctcat 11040
gtagcaactg ggagatggtt atctaatcac ctattatggc ctgactacaa gcatcaggca 11100
gaacaatgca ttactataca gcaaggaact ttctatcctt gccttagaga aatggtctcc 11160
ccacatattc taagatctac agggtgcctg agagttttgt attgtcccat ggcttgagta 11220
tccttccaaa tcattcatta aactccagtc cctagcaaat gaggtcattg atcctgttca 11280
ctcctttgtg ctcagctcct gtaatgtatc tcatagggtc ccatttctgt cttagtttac 11340
aggttttatt acctcaagtt tctttccttg tttgcacaga tagataggca catggctttg 11400
gtgcaaatat tctctaagca ttcataatgg tgctaccact tctcccaccg tgcttcaaaa 11460
acacacaaaa gaaaaccagc taaaagcctt cctagatgaa actgctactt ttataccact 11520
taattctcat ggtttttttt gggggggggt ggtctatttg atttttttca gaaacatgag 11580
cagggagggg atgcacatat gccctatcga ttagcctctc ctcttgagtc tggtgtttgt 11640
gtggaaagag ttttcatagt ttaagagaga ttgtgaggtt tttgcaaagg tgcttggcac 11700
ttcagtttag atgcgaagca attattaggg ctctgagaag ttcaaaagaa aggtagatga 11760
ctctgagtca tctaccatat caataaatta taactggtaa ataacactgt tatccataga 11820
ttacacattc taatgttagg aaaatgtatg aaataaatat tatatgaacc caataggaag 11880
aaagagagga aaacaaacca tgaacagaaa aacagaccat gtagctttta cagagaccaa 11940
acttggaagt gtaaagttat gcatgtatgt tcatgtatat gagtttgtgt gctttaatga 12000
gacaaaatga gtggccagaa ttgctttatt cagggtcttg aagtattcat gttgttaatt 12060
tctgcaattg tttttaggtt ttgagagtaa tgcatatatt ctaaatctca tagaacatgc 12120
ttctgggtcc atcaacattg gtgcttcctt aaattaaacc tcttgatggg ggttttcatt 12180
attattcaac ctctaatgag tgttgtcttc atgctagatg gtacgtggga aaaaagaaac 12240
ccatattctt tttggtaaga gagaatgcta ttaatttaca gtgcatatat ttatacctga 12300
aaacatgttc cagaaagcag tcacggccaa tgtgttctcc ttgctctggg ctctgcttaa 12360
aggataatca ttttatctgt cccagtgttt ggttcttatg ttcaaatgcc agaaagtttt 12420
ttaagagtta gacagagctg taactcaaat aatcacattt aatccagctt cctacttcta 12480
ttttcattaa cctattgtat attaactcaa ccactatacc attgctatac caataattgt 12540
atatacattt atagataaat tttttaaccc actcaagcaa ctcatatatg aaatacaggt 12600
gttatcaacc ctcataatat tttttgtaat aatttttctg acatatgttg agaccagttt 12660
gatgggtctc ctgttctgca gcatatagac accagcattt ctacagaggt taaaacctag 12720
aagaaaattt acagaccatc aacactctca cttcacaaat aagaaacctg gggaccatca 12780
aggcagaaga aaacccagat ctcttgactt tagtccagtc caacaaattg tactaaacag 12840
atttaatagt taattcttaa cctggtaagg gagaaagtgt ctgagacagc tctcaatcaa 12900
tttagaggtt tattttacca aggttgagga tgcaactgag aaaaagagac ctaggttgca 12960
gtagcatctg tgatctgtgc tttttccaaa gaggtgtttg aaggcttcaa tatttaaagg 13020
gggaagagca gcaggagaga aggaggaaag aaaaaaatag ggagggtagg gagtaaggta 13080
agtggtcact ttcttgtgag ggtttgatca gtactcactg aatccacatg ttatatgtaa 13140
aaggaggggg gccacatgga gaaatagtgg ccttctgtca ttgcacctat ctgtttaggt 13200
acaaaaggga aggcagtttt tgtgtgaccc agttctcaag tgtaactctt ccttttaaca 13260
tagtgagttt ggagtcccag gattttattt tcctttcaca ggagagatta ggtacttagc 13320
aatgactagc tatttgaaaa tctaacctta tcagattatt aaccttgtct cctttcataa 13380
ataacatgtt aaggtaacac agaagcttaa tactttaagc tgattggatg gcagtagaat 13440
gaatgtaatt caagtaggaa ctggaagatc cagtgtgtca ggtttagaaa ctaggaggtg 13500
gcaggaagca aaggttaatg tttaccaatg atccatagta agccaacagt acagatcaac 13560
aaacttaaaa tgtgtgagaa aatacaggga attgaggtat tttttgcttg gaaaaaagaa 13620
tttgattgtg cttattgcca ttttcgtata ttttctgatg ggcaaacaat agaatatttg 13680
ccctcaaagc gccaatggtt gaaagcttca gagagtgatt tcttggctca gtgtaagagc 13740
ctgttggctg ggcctggtgg ctcacgcctg taatcccagt actttgggag gccaactggg 13800
gccgatcacc tgaggtcagg agtttgagac cagcctggcc aacatagtga aacccggctt 13860
ttctaaaaac acaaaaatta gctgggcatg gtggcacaca cctgcaatcc cagctactcg 13920
ggaggctgat gcaggagaat ctcttgaacc tgggaggagg aggttgcagt gagccgagat 13980
cgggccattg cactccagcc tgggggacag agcaagactc catctcaaaa aaacaaaaaa 14040
caaaaaaaaa aaaacctgtc tataaataga aaataacttc cactccttgg gagataaaaa 14100
gtcattctag tggtgtcagc acaggttgga gaaatacttt acagatatgt tatggaaggg 14160
acttaggcac tgattttctt gtgtgtttgg gccatcaaac gtgctttcag tcttgaaatc 14220
ttgttttatg agtcaccttc tagaaaagag gtaggaatat ttttcggagt agtgtggcta 14280
ttaccatgtt tgctgtattg aggaagcggt attctaatgg ggtttctaga cctgcagaca 14340
actttgggaa tggattttaa ttgcttataa ctaaaaatga gtaaaaacta gtacttatat 14400
gcagcatcat agcagttaac tcctttacca gaaggatata gattataatc ataaactaat 14460
ctacaagatt tagaactact ttacataaac acagttatag tttggggcat cattttatta 14520
aaggcatttg ttaaatatat gattaaaaaa taaagtattc ttcataaata attttaccaa 14580
aatagcttac cccattgtat tgtatttaaa actttcagtg agcattgagc tattgttaaa 14640
gacagataag ttacagattc aagagaaggg agcatagtgt tagaacactg gagtgattgt 14700
cattaaaagc agagtaaaca agattgtttt ggctaattca ataaggttag aaacagcaaa 14760
acaagggata atgaaccaag tgaggacaaa actatcattg cagattaaat gactgtatac 14820
ttacaaaagc aaataaactt agttctaaag ccttataatt aataagaatg cagcaatggg 14880
cttaaacagg taaaatagaa aaaaagcagt atgttaggtt cttattttgt tttgttgttg 14940
ttaacgtttg agtgttttcc attcccaatt ttgattattt acaatctaca taaaagtcca 15000
tggcatgtgt ttatctgtaa ttttgctgaa gggcaaattt gtatcttgcc agtttttgtg 15060
ccattttggt ctgcaatctc ttaatcagtg aataagtttc ctcctgacag tcatgctgta 15120
taaaactttg caatttaata tacacagtca tgcaactctg gtgtaggtga cttgttgtta 15180
tcttcatttt atagatagtg aacctaataa tatatgcctg aaggggattg ggggggttgc 15240
agggattgag atcaattcct tgggtctcct tcagcttgat ctctattaac aataacaatc 15300
tgagagaaac gacgaaaaaa tatttggtta attagctaat aatatatttt attcaaaata 15360
taaaaaattt aaagaaaagt tcaaatgttt gctaagaata attcaaaaag acttaaaaag 15420
ctaataacat ataatactga tgaggttaca gtgatatgga agttttcatg tgcaaaaggt 15480
aaaggtatga aattaaaatt tccctgaaag taatttggca ttatatagca agaacagttc 15540
tgattttcat ctaatatgcc ctggcctggc cctgctggtt gttaaaaata ttgaaattct 15600
tgataaacag ctactcttct tccatattat cacagcccca gatactgctt cagtgctttc 15660
tcctggatat cccaccttgc ctccccaccc cccatctcca gggctccagc aattggcctg 15720
gccttgccag tccaggaggg ctgctaggac tgtgctacag ttcctcagcc tgcatccttt 15780
ctgagcacct gccacccttg gacttgagct ttttgtggtg gttgttattg ttgtttatca 15840
ctgtttttaa aaatatcatc agagatcaag agtcttattc caatcattaa ttcccattat 15900
ggaaattaac ttaaaaaagt aagatttttg cacaaaaatt tatggctcat tttcagtctc 15960
ctcacaatac caaaatatct aaaactatat atgagaccaa cgatagtgaa ttttaagtat 16020
atttatatac gtatatatta actatactac agttatgtat gtatatatta actgtaatat 16080
aatattacat aattatataa tatatgatta tataatatag tattatacaa tacatatgat 16140
tatataatat agtattatac aatacatatg attatataat atagtattat atacaataca 16200
tatgattaga taatatagta ttatacaata catatgatta gataatatag tattatacaa 16260
tacatatgat tatataatat agtattatac aatacatatg attagataat atagtattat 16320
acaatacata tgactagata atatagtatt atacaataca tatgatataa tatagtatta 16380
tacaatacat atgattagat aatatagtat tatacaatac atatgattag ataatatagt 16440
attatacaat acatatgatt agataatata gtattataca atacatatga ttatataata 16500
tagtattata caatacatat gattatataa tatagtatta tataatactt tataattatg 16560
taatatagta ttatataata ctttataatt atgtaatata gtataattat ataatttagt 16620
attatataat agtcttatat aataaatagt ataaagtata ctccatatta cataattata 16680
ataggtagta tacataaaat aggtaatcta ttatattaca tataataagt aatatataat 16740
atatataatt ggtaatacat tatataatat tcttatataa tatactatat aggcatacta 16800
taatagtaaa ttgtataata tatagcatag ttcatatatg tttatagtat agttatatat 16860
attatgtgtt atatatagta cataatatat aaagtataat ttatgttata taagacaaac 16920
tatatgtaaa attatatatt cacatataaa atatatccat atatatttcc atatataaag 16980
tatatataaa tacaaatata aatgaatttt acataaatgt atacttttat ttatttattt 17040
atttattttg agacggagtc ttgctctgtc gcccaggctg gagtgcagtg gtgtgatctc 17100
ggctcactgc aagctccgcc tcccgggttc acgccattct cctgcctcag cctcccgcgt 17160
agctgggact acaggcgccc atcaccacgt ttttagtaga gacggggttt caccctgtta 17220
gccaagatgg tctcgatctc ctgacctcgt gatccaccca ccttggcctc ccaaagtgct 17280
gggattatag gcgtgagcca ccacgcccgg ccatactttt attttattta tattatatat 17340
gaaagattaa taattaaatg aattatttca catgtccatt taagagaata tagtatagcc 17400
actacaaata acacattaaa ataaattttg atatattcat agtttaacac tcaagagaaa 17460
ggcaaaataa tttatataca taataatctc acctagatag actaagaaaa aaattgattt 17520
gatcaatgga gaaaaataaa agtttaggaa gcagtgagat gtttcttttc tactttttac 17580
ctttctctat gtcctgagtt ttctgcatta ttaattttta gccagagaga gaaaaaaaca 17640
aaactataat tttatatacg agagatgatg gtaaggacta gacctccggc ctctccttca 17700
tctccttcag ctaaacagct gaagcccaaa gcactgctcc cacaagtgtg ttttcctgac 17760
agtttttctt cagaagattt tgattcacct gtaacaggtt tttttttttt ttttgagaca 17820
gagtctccct ctgtcaccca ggctggagtg cagtggcacg atctcagctc actgcaagct 17880
ccaccaccca ggttcatgcc attctcctgc ctcgccctcc ccagtagctg ggactacagg 17940
cgtcagccac cacacccagc taatttttaa atatttttta gtagagacgg ggtttcactg 18000
tgttagccag gatggtctcg atctcctgac ctcatgatcc tcccatctcg gcctcccaaa 18060
gtgctgggat tacaggcgtg agccaccatg cccggtcctg taacagtttt atacctgtgc 18120
aaatatttaa agagcaatcc cagctatgtt gtagattagc agagcttttc ttcagagcct 18180
atagattctc agtgcctagc accgagtata cttcagctct gaggacagtg aggatgatgc 18240
tgatcaagag aatggtggct atcctctgtt tcttgaggta tttgttgtat cttttctgag 18300
ttttccatca aatatctgta catttcagtc ttcagcaccc tttgaagcat tttctctaag 18360
tttgtgtttt gtagaacatt ttggttgcat gacttttctt agacttcctg atgttgcaaa 18420
accctcaggc agtagatttc ctgggccaag aaccagaaga cacatgaaaa caaatggcaa 18480
cacccttttg actaagaatt tatatttata acccccttct tgaaactcta cagctatttt 18540
aatattttat actcatattt tcatatagac agaactgctt taatactgag gtacccaggg 18600
tgttggaggg agatagagag agaaaaagag aagtaaagaa aagaaaggat cttgtcagga 18660
atcttctgtc tttcatattg cagttcacaa tcagattgtt ctttctctgg ctgcaaaccc 18720
acacctgaaa ttatttttca tctccaagca cggagttata tgagcaatcg ctcttcctag 18780
aaaccatttt ttttctgcct gatattctag tagagggaac aaaaatgata ataatcttaa 18840
tgcaacatgt aatagaatta aatttttcct gctgataata tatattttga tatgagaaaa 18900
gaagcaggga taggctgaaa tcgaatggca ggagatatgg ccacagtctt taatccccta 18960
ttttcttgac ctgcagattg tctcattcgg ggaagctcca gggttctcaa gcggaattcg 19020
tgtttcattt tgtgtagcac ccgtcagaaa gacaagccag gcatgaggat ccatgatgag 19080
cgctcttctg agttgccatt tggagctgcc cgtttagaaa gcaaatctgc atttccctca 19140
ttcctagttt ccttcatcct cttttaagtg tcatcttttc catgaagcct actagatcac 19200
acagttgaaa attgcaaagt cttcacaccg cagcttcccc tttctttgtt gctttggttt 19260
tctccgtggg acttcccacc atccgtaaaa ttaggtgttt ttgcctgttt tattcactgc 19320
tacgtctcca atggttagaa cctgacattt agtgggtgct caataatatt tgttgaagta 19380
atgtataata acttcacttt cttgagtaat tactatatat catgaactgt ggtaaattat 19440
ctccatataa tgcctgtaat ctttacaaca cctctaaccc tataacataa accatgttat 19500
acccatttta cacatatgca atttaaagga cagagagacc cacacatttg cataggataa 19560
ttctagtgaa taagaaattt gcgttctttt gtctctctac aggcttcttc ttattattat 19620
tatcactatt ttgaaacaga gtctttctct gtcacccagg ttggagtgca gtgccgcgat 19680
ctaggctcac tgcaacctcc gtctctcagg ctcatgtgat tcttgtgcct cagccacccg 19740
agtagctgag attacaggct cacgccacca cgcccagata atttttgtat ttttagtaga 19800
gatttcacca tgttggccag gctggtcacg aactcctggc ctcaagtgat ccaccagcct 19860
aggcctcccg aagtgctggg attacaggca ggagccactg cgcccagcct taattttttc 19920
ttttcacgat ttttttccat tttaaattaa atgcctttgg attttaaaaa atgcaacatt 19980
cctctgctat cttattaaac gtatccttga acttcaggga gtggagaata ggtgtctgga 20040
aaatgagaca ctgcttttct ttgtttttga acttaacaag ttccacattc agagatctca 20100
attacatgcc cttcattgaa tgtaagtgtg atgcatttaa catacagctt gtgtgaaagc 20160
aggatattat aaccacaaac atatctgact ttaaaattaa gtaaaatact caacatagcc 20220
cagaatggaa acatgggaat taattctata tctgtggcag atctgaggga cacggtggta 20280
ccaaaaattg agatttacag agaaggagat ttttaataat tcagttttca ttaacttccc 20340
aaatcagaaa gccagcatat tctgtttggt aggaaattac acaggagtga agaaaaaaat 20400
ccacaattca gctgattaga aaacaagttt tcattaaact aaaatttatt gaatttttaa 20460
gcaatgtata gccagctagc ttccaaaaat ttgctcatcg atattgctta ataaaaagtg 20520
ttttctttcc ctttatatgc tgtaataaca taaactgcct aagtgctatt ttggaagctg 20580
aatcatagag gggctaagtg ttatgaaggc ttattatttt ccagacactt tgctagccac 20640
ttgacatatg taatcacatt ttattctaat ggaaactctg tggggacttc ctttaaaaat 20700
gaaagagctg aggttcagat attttgaggc tcagatggtt taagatgcat ttcatcaagt 20760
aatagacggt ggagccgatc tccaagccca ggttggattt ttcctgaagc gcatgatttt 20820
ttcctattat cccaaagcct catccataaa tatcatgcag aacctatgta gttgctcatt 20880
atagagaaag ttctagagcc taaagtagtc caaagtaagt gacccaaaac caggaagaca 20940
gttaacagta gaatacacag acttgcccaa ggggtatatc ctccacatcc tccacaaagt 21000
atttcctgct cttcttcttg gactcagcct cccctgtcct cactacagtc actaactctg 21060
cttttgtatt ttcactgttt gccctgaaga attccattat accattgttg taatttattg 21120
cacttaatgt gttttatgtt tccgattacc aatctgtaca tttttattct cctattgtat 21180
atttttatac aatatacata tagtgtatac aatatatatt gtagggaaca aaaaaaaatt 21240
ccccctcaac cctcatgaat tcttagctgg gatgggtccc tataacaaaa gatagattaa 21300
taagagggaa acaaacacgt ttattaacgt gcagtgctca tcatacagga tacactccaa 21360
ggaaaagtaa ctcgaagtag tggtttggaa ctctggctca tagagcatct tcaacaaaaa 21420
acaataaatt tgtggggaaa tgacaggaca aaggaaaatt attttaggct tccaagggag 21480
ggaaactgtg ggaaggtaaa tatatgggtg gaaaatatga gtaagtttgt ttgcagattc 21540
ctctggtgct gtctctggga cggtaagagt ttagagttgt ctccagtaaa ggagaattta 21600
taacctgccc ttaggcagaa gagtaggagg atagggaaaa ttttccttcc atttgctgct 21660
tcttaattgc ctttagctca aaaacaattt tcttgtcaaa gaggcagatg tcgaggtgac 21720
ctattctggt ttccctcaat atattactct ttcttgcatt gtcatggagt actataccct 21780
gaagattacc gtattgctaa gtattgatct gatctatgga ttctgactgt tacagaatac 21840
tgagtgttgt gcatccacca caatttttct gccttataac tttccatcta actcccttct 21900
atcccaagca atgctgtagt gaacgtggtt cagtatctcc ttatccaccc atgtgagaat 21960
ttctttggat tatgcatttt tattacattc tcaattcaga actcctgggt cgtaggttat 22020
gcatatattt aatacgaata agtattacca aattagtccc catagtggct gctccagtct 22080
atattctcag tggcctggat gaagtttctc tatctgaata tccctgacat cacttagcat 22140
tctttagctt tctgatgttt tgcaagtcca acaagcatca ggtgatattg tattgccatt 22200
ttaattttca tctctttgat tattaatgag tttgagcaat gtcaatgtgc ctattaactt 22260
tttaagaaat tatctctata agcccaacag tgggcatttc ctggcatata atggatcctt 22320
agtggatgta tgattgaaag aaagacatta tagcatgcaa aattcccaaa ttagtctcag 22380
gctttgattt ttgatacttg ttggttatct cgaaatctga acactaagta aatattggaa 22440
ttaagttttt gaggtaatta actatattaa tcagttgtcc tgattttaca gtcgaagatt 22500
gttggtaagt ttgacatagg gaaattaaac ttaaaaaaat cataaaaata acatttttta 22560
aaagttacca tatgatgtaa ggagtgactg tgagttatat tttcccattt tgtagatgag 22620
caaatgagtt caggagagat ttaaataccc tatgaaaagc atgcagaatt ctggtagcac 22680
tataaggata aataaaaaga ttgggccatt tggctagggc tggcatgagt taattataat 22740
cattatgtga ttaataaaac atttgacata ccagcaatca tgtcatgaag ttctattctc 22800
tgcctttgaa tagtagcaaa ctaggattat aattttataa tgacagacca gtttaagata 22860
gaagagacat gacacgtaag actctcagct tctcactatc tgcctaaaac gtgcatggac 22920
aaaattggtg tgtgctaaag gcagtgccac aggaaccgaa actaaaaaaa aaaaaaaaga 22980
ttaagaatgt ataaaactgc tctaactcca tcccttgact gccttgggat ctcaaatagc 23040
agaaatgtat gtccatcaac aatgcaagtg gaagtgtatg tctaatttaa agccgtgtcc 23100
taagaatagg atttcacata atgtgctagc taaagcgtag agggttggta gagcttttgt 23160
tagggatttc cttgcagcct atcttcacat cctacccttt aaacatgctt ttttaaatgt 23220
aacagcagag cacctagaaa acctattttt ccaagttgtg acttctctct ttcctacata 23280
cttttattct tctagtcatc caagtaacta tcttactagt agcagtctgt gagtctgtct 23340
atgcattcat gcatccgtct aaccagctgt ctacctactt atccatattt tttaagcaat 23400
aaaaatttca ttttgtagcc tcttttacta gtgcacttgc ccagaacaga cagtctccca 23460
ctcagaagac cagttctttg agtcaccaga taaagttcat atatgatata aggtatagtc 23520
acatcttcag tatactaaca tttactataa tacagcaatg ccttttaaaa tcaaatacac 23580
gtgattttac aaaaccaaat gtaagcctcc aggatgtaag agaacaactt gcattataaa 23640
gtatccttga acccaggagg cagagcttgc agtgagccaa aatcacacca ctgcactcca 23700
gcctgggcga cagagcgaga ctccatctca aaaaataaaa taaaattaaa attaaataaa 23760
aatgtttaat tagatacata atggtaaatg tggtactagt gttagtggta aatatggtaa 23820
ttagcgtaga gaggttaaat gattacagta agctaaaggc caaattgttg ttaatttgag 23880
ttgttttata tatgttgata aatgccttgg aatagtcact tgcatacaaa ataataaaag 23940
aaaaaattta gacctgtagt aattagtcag ggttctctag agaaacagaa ccaacgagat 24000
tatatatata taatataaat acaatttata tatatatacc ttaatatgta aaataaggaa 24060
ttagcttata tgattatgaa ggctgacaag tcccaagatc tgcagtcggt aggctggaga 24120
cccaggagag cccatggtgt aagttctagt ctcaaagcca gcaggcctga aggcttgaga 24180
ctcaacaaag gctgatattt cagtctgagt ctgaaggcca gaaatgacca gttccagctc 24240
aagctgttct cttctggtct tggattgatt ggatgaggga gggcagtctg ctttactcag 24300
tctaccaatt caaacattaa tctcatccaa aaatgccctg acagacacac ccagaatcat 24360
gtttatccaa atgtctgagc actccatggc ccagtagaga tgacacataa aagtaaccat 24420
cacagaaagg ttttctaatt ggaagataaa cacttcgaaa ataattaatt tgaataaatt 24480
tttatagaaa catttcaaat tatagataaa aaaagagaat taaaaataag ctataattct 24540
atcgccatta gataactctt gatttgaatt tggtgcatat ctttctaaac attgtatatt 24600
gaaatgaagt gctgtgtatc ccattgattt atgctgatac atacttggat ttgcccagct 24660
ttgctaaaat tacacacaag ggatcaattg agaaaatcag ttacatcatc atcacaagca 24720
cagaatgaaa aatcattaat ttgccttgct attcacagaa ggggagaaaa gaaaaaaaga 24780
aagaaaatac tatgatatgt ttgaatagag tttgtttaat catcaaaatt atttctctat 24840
ttgtcacaga aaatgctgta gcctttgttt ctttagggag aaacatttaa tgtcatttct 24900
taatagggct tttgttaacc caaacagctg ttggtgtgta tgtatctaaa ggccttaggg 24960
ggtcaaaaat aagtagcctt caatcatcag agttatgacc aagcaatggt catgagaggt 25020
cacatgtggg aagagactga ctataaactg agcatgtatt gccctactcc ccttaaatgc 25080
cattttctgg atctcaagtt taagattcct agaaagtttt gcaatgtaca ataaaagtag 25140
attgctgctt ccacattttt ttcacttacc cctgaatttg ttgagaattt ctgaattatt 25200
tgactcaagt ctagtttact ttctgccatt attttgacac attagtttgg cttgtgttct 25260
ctctgaaagc atttgtaagg cattccatac ctgattctgg aacatagtca taacattgtg 25320
ggtcctgctc tgaaggattc agttagaaag gacaatggcc actttttttt tttttttttt 25380
tttttttttt actttgaatc tcttatactg atggcttatg gttctatagg gtatagtaac 25440
ccctcatatg cctgcaaaga ttaatgatca aatcagctca gttattcaat ccagcattta 25500
agtatcctta gttcttttta acaaacttgt tggaagcaag cctttgctag tacatcatat 25560
aaatgaagaa gagcaataat ttagatcagg aaagacaagt gtgttttatc tgtgttgcca 25620
actccagtca attgatgggt agttagtgtc tggaagattc tcatgctgct tctgggctct 25680
gtgggaaaga ccactaagat taccagctat gagtggtaga gttttagatg tgtaggagtt 25740
agccagctga agtgaagaag tgagggagac ctttttaggc agaggagaaa gcatgggaga 25800
ggatggtacg taaaggaaag agggtagaat gcaagcaatt cagggctcct ggagccgcaa 25860
aattcagaat ataaaactgt gagtgatgag aataaggacc aggccagata gtctatgttt 25920
agtggagaag cttgaccttc atccatttta tagtcactag aagattttaa gcagggaagt 25980
gataggtttg cttagcaggg tttaaaatgg ttatcatggt aagtgctttg aggaatacaa 26040
gaccagaggt aggctgacct tttaggatat tattgcagta ttccaaatgt gaataatctt 26100
gacctgaata agagcacagc tagtagggac agaattgaga aagtaaactt cttgatggcc 26160
aggaaaggaa gataaaggaa gaagaaactt tgagtgatga tggatagcaa acagcatggg 26220
tgaatgtttc aagaaaagat aatactttaa aactaaatgt taaatggtta aacaagacta 26280
taatatgaca gatctgaact attgaccccc ctttttttta aacaggcaag aggattatat 26340
acatcttttt gttggccgga cgtggttact cacgcctgta atcccagcac tttgggaggc 26400
caaggtaggc agatcacttg aggtcaagag ttcgagacca gcctggccaa tatggtgaaa 26460
ccccgtctct actaaaaata tgaaaattag cctggcatgg tggtacgtgt ctgtaatccc 26520
agctacttgg gagggtgagg caggagaatc gcttgaacct gggaggcaga ggttgtagtg 26580
agccgagatt gcaccactgc actccagcct gggcaacaga gcaagactgt ttcaaaaaaa 26640
taaaaataaa tatttttgtc attgttgttt tattttaaag aaaggttttt taaaggaagt 26700
ttagggtttg cagataaatt gacagcaagg tacagagatt ttccatacaa cccctgctct 26760
caagcatgca ttgtctcccc attatatata tattccctcc cagaattaca atctgctaca 26820
atttataaac atccattgac atataattac tagaagctca tagtttactt tagggtttcc 26880
ttttggtgtt gtattccacg ggtttaaaca aatgtataaa gacatgtatc caccattaca 26940
gtattataca gagtagtttt actgtccccg aaatcatcta tgctccaccc cttcacatcc 27000
acccctcagc ccctggcaac cactgatctt ttcactgttt ccataatttt gtcttttcca 27060
gaatgtcatc tagttgaaat cacacagcat gtaacctttt catattggct ccgttcagat 27120
agtaatatgc atttaagttt cttccatgtc ttttcatggc ttagtaactc atttctttct 27180
tgtactgaat gatattctat tgtctgcatg taccacagat tctttgtttg tttgttcttt 27240
tacttatcag tttatatgct gaaggacaca tcttggttac ttccaagctt tggcaattat 27300
gaataaagct aataaacatc tatgtgcaga tttttgtgtg actgtaagtt ttcaactcct 27360
ttgggtagaa accaaggagc ttgattactg aatcatatgg taaggttatg cttcgtcttt 27420
taagaaactg ccaaactgta ttccaaagtg gacccaaagt tacctttccc accagcagcg 27480
aatgagagtt cctgttgctc catatctttc ccagcatttg ttgtcattag tgctctggat 27540
tttggccctt ccaggtgtgt aatggtattt tgttaatgtt ttaatttgca tttcattgat 27600
ggcatatgat atgaaatatc tctttatata tttatctgtc atctgtatat cttctttggt 27660
gaggtgttta ggtctttggc ccaattgtta attgggctgg ttgttttctt atcgttgagc 27720
tttaagagtt ctttgtatat tttggatagt aatcctttat cagatatgct cttttcaatt 27780
attttctttc atgcttgtca tctcattctc ttgacatttt cttttgtaga gcagaagttt 27840
ttaattttaa taaagttcag cttattaatt acttatttca tagattatgc ctttggtttc 27900
tatttaaaaa gtcatcgccg tacccaaggt catctaggtt ttcctctgtg ttatatttta 27960
ggaattttac agttttatgt tttacacata gttctatgat tcattttgag ttaatttttg 28020
tgaaggatgt aaggtccttg tctagattca tttttttgca ggtgggtatc cagttgttgc 28080
agcaccattt gttgaaaaga ctatctttgc tccattgtat tgcctttgct cccttgtcaa 28140
agatcaattc actatattta tgtgggtcta tttctggtct ctctattctg ttccactgat 28200
ctatctgtct attcttttgc cattaccagg ctgttttgat tcatatagct ttatagtaag 28260
tcttgaagtc agatagtgtc ggttctccaa ctttattctt ctctttccat attatattgc 28320
agattatggg tataaattat tttttaaaaa tacatgtctg ctatttctga gggatactga 28380
aaagcaaatc atgtagaata caatgtcaag gaatatttta ttttatgatt ttatatctta 28440
tggatatgta tatataccca cacatattta tatgtacata catatgtata tgttctgagg 28500
gaaaaactca aactttttcc tctgctctca caccacaaca atcaacacag aagacttctg 28560
tgaccaaatg catgagtttt ttttttctcc caacaccaag cagcagatac ttccaggtat 28620
cttccaattc aattcaattc tgatgctgtc tccctgaaaa taatgtcaga tcccacaggt 28680
tgagggctca gtcccacaaa actgtcccct ttcagacacc agttgcaagt ttgggcctcc 28740
agaatttctc agtagccagc ttcaagttga ggtttccaca acccctcttt gggtttgatt 28800
aatttactaa agtggttcac agaactcagg gaaactggct taatttgctg gtttatgata 28860
aaggatgtta caaaggctac agatgaagag atgcataggg taaggtatga gagaaggtac 28920
acagagcttt catgctctgc ctggatatgc cacctgccag gatcctacac atgttcacta 28980
tctggaagct cttcaaatcc tgttctcttg ggccttttat gaaaacttca ttggataggc 29040
atgactgaag catggacaac catgtagtaa tgtgattgga tgaaaaggtt ataatctaat 29100
gctgataggc tgagtgggaa aacccagtga ggcctatctg ttcagattct tcttgatctc 29160
tctgtgcagc attaattcct ctaggatatg ggacaggacc tcctctgaaa tgaggtctta 29220
tgaccctcaa tcacaaaggt ggaaacacgt tatagtcctg ccttgtatag gtgaaaggtt 29280
ttctgaggtc tgctcctgag gccaaaagca ccataaaatt ataataaaag actattaaca 29340
agggctatgg gaatcataag ccaggagcca tagataaaaa catatagata tataaaataa 29400
tatcacacac atatatcgat ctatgcatat acacacattt ctataaagat acatatatgt 29460
atgtaaatag atagaagtag atatttatat agctagatat agaagtagat aattgtatta 29520
tttattacat atatatcaca ataagaaata ctatacttat tataaaaata acacagggcg 29580
gggccaagat ggccgactag aaacagcagc gtttggaggc ccccattgaa aaaaaacata 29640
agcttgtgaa tacttcacca gcaaccaagg catccaggtt ctctcatcag aactgactag 29700
gaggttggtg tgacccacgg agagaaagaa gaacagtgtg gtgtggcagc ccacatgaga 29760
gccacatgga gtgggggagc cccctccccc ccagccaagg gaggcaatgg gtgagcgtgc 29820
tttttccaca gaattgtgca acccacagat tggaagatcc cactcgtgaa cccacaccac 29880
cagggactag cgtcccaacc caggaatgca cagactctta gcttctcggt tggaaggaat 29940
ctgcttaagc ctacggaact cctggaggga ggggtgacca gaactgggtg tggctgcctg 30000
ctgtcaaagc tatttgagct ccttgtggga ggagcagcag ccagtactgg gatttgcatc 30060
tgcctaacac aaagctccct gggcagggga agggaggcat ccatctctat agccccaggc 30120
tgtgcttttc ctctgttgga gacagggagg ctggacggct tggtcccaag acttgtccct 30180
cacagtccaa cacatctgct tgcagtctgt ggccagagtg cctcttcagg cctgaccctg 30240
acccatcctt cctcattggg tgaggcttcc cccaccaact ccagtaacac cagccagagg 30300
ctcagggaca gaacctgcat ctccctggtc ctgtgtccct agggggaggg atggctgcag 30360
tctctgtgga ccagcagact tagcctttcc tcctggtagt tctgaggaat ccaggcagcc 30420
cagacaagtg ggttccccgc aagtgaggca ctgtgttaaa caggttctgt tccccatgcc 30480
acccaactgg gtgagaccct ccaatagagg ttgtcagaca ccctatacag gagtgctcct 30540
actggcatca ggctggtgcc cctcaaggtc agaagtccca gaagaagaag caggcactca 30600
tctttgctgt tctccagcct ctttgagtga catctccagg cacagcagcg aatcagataa 30660
ataggtcctg aagtgaaccc ccagcaaact gcagcagccc tacagaagag ggacctaacc 30720
attgaaagaa aaaaaacaag cagaaagcaa caacaacagc atcaacaaca agaacaacaa 30780
aaagtctcca caaaaactcc atccaagggt cagcagcctc aaagaccaaa actagacaaa 30840
ctcacgaagt caagaaagaa tcaatgaaac aatgctgaaa acccaaaagg tcagagtgcc 30900
ttttgtcctc caaatgattt caacctttct ccgtcggggt aacagaactg gagggaggat 30960
cagatggaca aattgacaga agtaggcttc aaaatatggg taataaaaac ctacactgat 31020
ctaaaggagc atgttctaac ccaatgcaaa gaagctaaga accttgataa aaggttagag 31080
gaattgctaa ctagaataac cagtttagag aggagcataa acaacatgtt ggagctgaaa 31140
aacacagcac gagaacttcc tgaagcatac acaagtatca actgatgaat caaccaagtg 31200
gaagaaagaa tatcagagtc tgaagacaag actagagaaa aaagaatgaa aaggaatgaa 31260
caaagcttcc aagaaatatg agacttcata agaagaccaa acctacaatt gattggagtc 31320
caagaaggag atggagagaa tggaaacaag ctggaaaaca cacttcagga tattatccag 31380
gagaacttcc tcaatctagc aagactgcca acatgcaaac tgaggaaaaa cagagaacat 31440
cattaagata ctccacaaga aattcaaccc caagacacat aatcatcaga ttgaagattg 31500
aaatgaaaga aaattgttaa gggcagccaa agagaaaagc caggtcacct acaaagggaa 31560
acccatcaga ctgacagacc tctcagcaga aactctacaa gccagaaaag attgggggcc 31620
aatattcaac attcttaaag aaaaaaaaaa ttcaacctag aatttcatat ccagccaaac 31680
tagcttcata agcaaaggag aaataaaatc ctttccagac aagcaaatgc tgaggaattt 31740
tgttgttacc aggcctgccc tgcaagagct cctgaaggaa gcactaaaga tggaaaggaa 31800
aagccaggag cagccactgc aaaaacacat caaaatataa agaccaatga cactatgaag 31860
aaactgcaac aactagtgta caaaataaac aaatagcagc atgatggtag ggtcaaattc 31920
acacataatg atactaacct taaatgtaaa tgagctaaat gtcccaatta aaagacacag 31980
tctgacaaat cggataaaga gtcaagaccc atcacccatc agtgtgctgt attcaggaga 32040
cccatctcat gtgcaaagac atgcataggc tcaaaataag gggatggagg aaaatttacc 32100
aagcaaatgg aaagcaaaaa ataagcaggg gttgaaatcc tagtctctga caaaacagac 32160
tttaaaccaa caaagatcaa aaaagacaag ggcattacat aaggtaaagg gaacaattca 32220
acaagaagag ctaactattc taaatatata tgcaccctat acaagagcac ccagattcat 32280
aaaacaagtt tttagagacc tacaaagaga ggtatactcc cagacaataa tagtgggaga 32340
ttttaacacc ccactgtcag tattagatca atgagacaga aaattaataa ggatattcaa 32400
gacttgaact cagatctgga tcaagtggac ctagtagaca tctacaaacc tctgtacccc 32460
aaatcaacag aatatacatt cttcgcaatg ccacttggca cttattctaa aatctacgac 32520
ataattggaa ataaaacact ccttagcaaa tgcaaaagaa ctgaaatcat aacagtctct 32580
cagaccacag tgcaatcaaa ttagaactca ggattaagaa actcactcaa aaccacataa 32640
ttacatggaa attgaacaac ctgctcctga atgactcctg ggtaaataat gaaattaaag 32700
cagagatcaa gaagttcttt gaaaccaaca agaacaaaga gacaacatac cagaatctct 32760
gggacacaac taaagcagtg ttaagaggga aatttatagc acttaaatgc ccccatcaga 32820
aagcctgaag atctcaagtt gacaccctaa catcacaatt aaaagagtta tagaggcaag 32880
aacaaatgaa tccaaaagct ggcagaagac tagaaataac tatgatcaga gaagaattaa 32940
aggagataga gacccaaaaa ccctccaaaa aaaaaatcaa tgagtccagg agctggtttt 33000
ttgaaaaaat taacaaaata gattgctagc tagactaata aaggagaaaa gagagaagga 33060
tcaaatagac acaataaaaa atgataaagg ggatatcacc actgacccca cagaaataca 33120
aactaccatc agagaatact ataaacacct ctacacaaat aaactagaaa ctctagaaga 33180
aatggttaaa ttcctgggca catacaccct actaagacta gaccaagaag aagttgaatc 33240
cctgaataga ccaataacaa gttctgaaat taaggcagta attaatagcc taccaaccaa 33300
agaaagccca ggaccagatg gattcacagc tgagtcctac cagaaataca aagaggagct 33360
ggtaccattc cttcagatac tattacaaat gattgaaaag gtgggactct tccctaactc 33420
attttatgaa gccagcatct tcctgataac gaaatcaaga agagacacaa caaaaaaaag 33480
gaaacttcag gccagtatct ctgatgaata tcgatgggaa aatcctcaat aaaatactgg 33540
caaaccaaat tcagcagcac attaaaaaaa attatccacc acaatcaagt cagcttcatc 33600
cctgggatgc aaggctggtt caacatacac aaatcaaaaa acataatcta tcacataaac 33660
agaccgaaag acaaaaacca cattattatc tcaatagatg cagaaaaggc ctttgataaa 33720
attaaactac tcttcttgtt aaaaactctc aataaactag atattaatgg aacatatctc 33780
aaaataatga aagctatgta tgacaaactt acccaaccaa tatcatattg aataggcaaa 33840
agctggaagc attcctgttg aaaaccagta caagacaagg atgtcctctc tcaccactcc 33900
tattcaacat agtattggaa gttcttgcca gggcaatcaa gcaatagaaa caaataaaag 33960
gtattcaaat aggaagagag gaagtcaaat tgtctctgtt tgtagacaac atgattgtat 34020
atttagaaaa ccccatcatc tcagcctaaa aacttcttaa actgataagc aacttcagca 34080
aagtcttagg atacaaaatc aatgtgcaaa aatcacaagc attcctttac accaacaata 34140
gacaaaaaca gagccaaatc atgaataaac tccaaatcac agttgctaca aagagaataa 34200
aatacctagg aatacagcta acaagggatg caaaggacct cttcaaggag atctacaaag 34260
catttttcaa ggatataaga gaggatgcaa tcaaatggaa aaacattcca tcctcatgga 34320
taagaagaat caatattatg aaaatgacca tactgcccaa attgatttat agattcaatg 34380
ctattcccat caaactacca tcgacattct tcacagaatt agaaaaagtt attttaaatt 34440
tcatatgtaa tcaaagaaga ccacatatag ccaagacaat cctaagcaaa aggagcaaag 34500
ctggaggcat catgccacct gacttcaaac tatactaaaa gtctacagta accaaaacag 34560
catggtactg gtaccaaaac agatatatag accaatggaa cagaacagag acctcagaaa 34620
taacaccaca cacctacaac catctgatct tcaacaaacc tgacaaaaac aagcaacggg 34680
gaaaggatct cctattcagt aaatggtgct gggaaaactg gctagccata tgcagaaaac 34740
tgaaactcga ccccttcctt acaccttata acaaaaatta acccaagatg gattaaagac 34800
ttaaatgtaa aacccaaaac cataaaaacc ctagaagaca acctaggcaa taccattcag 34860
gacataggca tgggcaaaga cttcatgaca aaaatgccaa aagcaattgc aacaaaagcc 34920
aacatttaca aatgggatct aattaaacta aagaacttct gcacagcaaa agaaactatc 34980
atcagagtga acaggcaacc tacagaatgg gataaaattt ctgtgctcta cccatctgac 35040
aaagatctaa tatccagaat ttacaaggaa cttaaatgaa tttataagaa aaaaaaagcc 35100
accccatcaa aaactggaca aaagatatga acagacactt ctcaaaagaa gacatttatg 35160
tggccaacaa acatatgaaa aaaagctcaa tatcgctgat catcagagaa atgcaaatca 35220
aaaccaccat gagataccat ctcatgccag tcagaatggc aattattaaa acatcaggaa 35280
acaatagatg ctggcaaagc cgtggagaga taggagcact tttacattgt tggtgggaat 35340
gtcaattagt tcaaccattg tggaagacag tatggagatt cctcaagaat ttagaaccag 35400
aaataccatt tgacccagca atgggattgc tgggtatata cccaaaggaa tataaatcat 35460
tctactataa agacacatgc atatgtatgc tcactgcagc actatttaca atagcaaagt 35520
catggaacca acccaaatgc ccatcggtga tagactggat aaagaaaatg tgcatataca 35580
ccatgttata ctgtaaagcc ataaaaaaga atgagttcat gtccttcaca gggacatgga 35640
tgatgctggg agccatcatc ctcagcaaac taacaggaac agagaaccaa ataccgcatg 35700
ttctcattca taagtggcag ttgaacgatg agagcacatg gacacagagc ggggagcaac 35760
agacaccagg gcctgttggg ggttggggtt gaggggaggg aacacagaag acaggtcaat 35820
aggtgcagca aaccaccatg gtgcatgtat acctatgtaa caaacctgta cattctgcat 35880
atatattcca ttctttctca gaagaaataa aaaaaagcac agaatgtaat cgcctatgag 35940
cacagtggta ttatttattg tccaatgtag ggtactttag agaattagtt ggaaagagta 36000
ggtaaaataa ttaaaattat tataattttt gaaatttgta tgcattgaac aaatttctca 36060
tattagtaaa tttatgaaat gttctttttt aaaaactact tccaaaacta aaattctgct 36120
aatgatattt tattaaaaat gaacaagtta ggaccaaaaa acgaaagcag atggacacta 36180
agtcaacagg tataaaatgg aaatgtccct gacaaacaag tatggtcacc ctacttatga 36240
ggtcagaaat agattttacg ttctaattga ctcttaagga aatagttgca ttatcacctc 36300
ttcttaaact taatttattt ttgtcaggaa tccagcacac atgagcttat actctagagg 36360
ctgttatgca aaccaatggt ttccatatgt caattgtgat tctagcattg tgtcctctat 36420
cagtgcccca gggagaggga ctgcctggct ctgaacatgt cccagactgt gctagatata 36480
ttttgccaac caggccaacc tgaaatgtca aggtccatct ttggaggaga gctcatcaag 36540
ccctgagggg atataattgc atttcagtta tctttttcaa aatgtcgaat ttgagatcct 36600
cataattgat aatttttcat ttaaaatgta tggctaggtt aatatgaggc aagaacagaa 36660
aattttggtc tctagtcttt tgggggcaag ctggaatcta tttcccatta gcccacagct 36720
attcttacca gccttttgtc ttagttgtct ttttttccct tcagaatagt tgctgaacag 36780
aagaataaaa ggcttttcat gtctttttag catttgtgat ctttctactt cttagttgaa 36840
tgagttagaa gaataaacat tgtagattta gacaaatgtg acttaaactt caggtatatc 36900
aatatccctt gaatgtcaac atactcaaat cacctaatcc agttgggaat attaataata 36960
tcatggaact tgctgtcagg attaatgaga tgttccaggt aaaaagccta gcacagtgtt 37020
tggcaaatag taggtggcca ataataaatg gcagctatag tcatcagtga agaaatacat 37080
gatttcaagt aggtagggct ggctgtgaag aaaattgtca cataagtgac ttcatactct 37140
atttcagctt ccttcccact ctccctcctt ccctccacac acaccatgta cgccatctcc 37200
tattgtcagt acttgggact ctcatatgca cctggaccac tgtcttttcc cagtctagca 37260
tcttctgttc ctggtttatc ttcctcatct ctttccttcc agacctccca gtcttatgac 37320
ctctgctttt gcttcctgct atgtgcagcc ttggaaagtt tctgctaatg tcatttatgc 37380
caaatgttaa agactaacat cattttccta tgctaatctt gccaggaggt atttccattt 37440
tagtgaaggt caacatcata acctaactga ataaaagtgc aaaacataag ttggaggcat 37500
cagcaagagg gagagaagag atattttcaa atagatgtac tcaagataac aataaaaata 37560
atgaacagct aacatttatt cactgccaac tttattttgc actgtgcatt atatgcatta 37620
cttcatttaa ccctcacaac taataaatta agtactatta ttatttttat ttttctaata 37680
aaaaaaaaaa agaagcttgg agaggtaaag caaattgccc aaagtcgtat acaccgagta 37740
agtgaagaag acaggtttaa aactcaagtc catctgactt attgtcatct ctcttacact 37800
aacccttaca ggctgaattt tcaccagggc agggattctt gcttggaagt cctgccttgc 37860
tcaatattct aagaaatcta gactgctagt agttccaaat atactctttt attttctgtg 37920
tgtgcatctg tcatcttgtc ccctgtacct gcaatccctc acttccccac agtttctggg 37980
ctaactccca cttaccctgg gagtgacaga gttcatgagt gatcttcccc catgaagcat 38040
catcactctg gcatcatctc tcgtcctctc cccatatgtt ctcttccctc ttcctacctt 38100
gattcaactg agccagggct atttctgtgt ctgtgaacag gtaatagtgt ttatgagggc 38160
agatatctga catgtttttc ttctttattt tacctgacat atgcttgtac cctttattta 38220
atctgacatt tttttgtact cttctggcct agcctactct gccagttctg aggtgcattt 38280
ttttttcgta ttttaatacc tctgatattg ttatgctctc cagttgataa aaatcttaaa 38340
attttaattg acagtggctt ttttctaact tggtgaaaca aaaataaggg ttaatttcct 38400
tctacaatca acagcatctt tgatttgatg aaatatagtg atagatgtta aagatcatgt 38460
aaacgaatgg atggcactca cagccctcct tgagtcacat tactatgcct acttagaacc 38520
tagctgccct gcatcatggc agggcagcag ttgaacatta ttctttattt atgttaggct 38580
ttcctagtaa aggtagggca gataataaat cagctaaaat tgtttttaat catttcttgc 38640
tggaatgatg tgacctgtcc catatgttta tcttctaggt gaaattgatc ttcaaattct 38700
ctccaaagtt caggctcaat acccaggagt ttgtatcaac aatgaagttg ttgagccaag 38760
tgctgaacaa attgccaaat acaaaggtac ctgtaactcc tggtcctcta caccagatcc 38820
tatcccaaaa gacttaactc aaattgttcc cttgaatgat taaaaatata gttactgtgg 38880
tatgcttttc acaagcttat tgggagaaga actgaattag ttcttggcag gcatgactaa 38940
acatctcaaa atgtgaacag tgaataataa actccctttt ctattaacac ttcatccatt 39000
ccccagttgt catcaatgat taccttttga tgtttatgct taagtacaga ttcattcatt 39060
gatccagaat tatttaaacc aaccttaaag agcttatgtt tagtgggtta cagtaaaagt 39120
tcacaaactt ttcctggcaa aggccaaata gtaaatattt tagattcaga aggtcaattc 39180
agtctctgcc ataactaatc aacctgccat gtgccacaaa ggcagccaaa aagaaaaata 39240
ggtaaactaa caagcatggg tgtgtttgaa taaaacttta tttgtaaaca ctaaaatttg 39300
aatttcatat cattttcaca tatgaattag catccttctt ttgttttttt aaatcattca 39360
aaaatataat gacgtgaaac atgaatggca gtgacacaaa gtcaggaagt agaacgatat 39420
atgtttttag cttgcggttc atacaaaaat aagtagcagg ctagatatag tccctggact 39480
gtagtttgtc ttctcctgaa ttatacaaac atatctgttt ccaattcact ttccattgat 39540
aaaattcacc agttgattct tcattaatac taagacaata taacctattc tgcccagggt 39600
tcttgtaatt atttcttcct gactctttct ttcacctcta atttcattaa atactagaaa 39660
ccaaaaaaag cagtatgaac tctctggtct cccagacata agaaagaaaa acgttctttc 39720
tatctgtttg tatataacat tgattgcatt aaaattctaa atggaaatgg tttccacatt 39780
tgcaattaaa attgatggtg tgtcacctct tctctgtatt ttagagcttg tagccaagac 39840
atcgaacctc gagaacgtaa agtttgcttg gcataaggag acatcatctg aataccaaag 39900
tagaatgttg gagaaaaagg agcttcaaaa gtgggacttt attcatatga ttcaagtaag 39960
aaatatgtat tataatatat actcagaaag aagacttttc agaatatata tataatgaat 40020
atctactatt ctaattttta aaaggtaaat gaaaatcttc tgatttctaa ttttacaagt 40080
gaccatgatc tgcccaaata aaaggtaaag atgtttatta tactaagatt ctctttaaca 40140
ttccaaaaac cagttttctc taatcaaaat acctctacaa gttatccatt tttaaaaatg 40200
ttggcttaat tcttatttct tttttgagat gggagtctcg ctgtgtcatc caggctggag 40260
tgcggtggca tgatcttagc tcactctagc ctcaaaatcc tgagcttaag caattctccc 40320
actgcagctt cctggttagt tgagaccaca ggtgtgcacc accacaccca actaattttt 40380
tattttttgt agagatgggg tcatactatg ttgcccaggc tggtcttgaa atcctgggct 40440
caagtgatct tccctcttca acctccaaaa gtgttggaat tacaggtgtg agccactgca 40500
cccagtcttt aatttatttt tatatcattg gatgtttata tagagatttg agaatgatag 40560
catcataaca tattctctag tggctctaat ggtttgggtg gaccaatgtc ccagagtgtt 40620
tctgtagtgg acatatggtc gaaggggcag gttaaatgat gcctcagttc aataaatttt 40680
tacttccatt atccagatcc gacaaactga ctcatacatg ttatagaaag ggagtgacgc 40740
aagaacaaaa aaccaaacac cgcatattct cactcatagg tgggaattga acaatgagaa 40800
cacatggaca caggaaaggg aacatcacac tctggggtct gttgtggggt ggggggaggg 40860
gggagggata gcatcgggag atatacctaa tgctagatga cgagttagtg ggtgcagcgc 40920
accagcatgg cacatgtata catatgtaac taacctgcac attgtgcaca tgtaccctaa 40980
aacttaaagt ataataataa taataataaa agaaagggag tgactattga gtagatagca 41040
tggggctgga tttccagaga taactaacat ttctgaatag cataagggat gtatgggttt 41100
tggaagttgg ttaccaacgg gaaatgtacg tattttggca ataccacttg attaacgaca 41160
aaacactatt tttcttcctg gtctacaatg ataatcaccc caaaagaata aacttacaag 41220
aagtcaaagg aagaaatact ccaattgtgt catatacagg caattctatg tctctgcttc 41280
tttagctgat gaaatctttt gcctgtcagg tagtacttat cactgtccag gatgccaaga 41340
tatttctcta ccagacttgc ttttgttccc acttcctcac ataactattt cataactccc 41400
ctgtctcctt accactcctg caatctctcc cagaccattc gttctgagcc aatgacctca 41460
cttcataatg tatagagaaa atagaaactg ccagatactc attttttacc ctctaacttt 41520
gcaaacataa ctgcatttgt gcatcatctc cttcttccat cttattgcaa aaacctcctc 41580
ttatcaaaaa ccactccctc tgcttaaccc tggatcccat tcttttctct gttataaata 41640
ttgtgatttc aggaatcagc ttctctttcc tatttctctt aaaacttcca tgtttgttcc 41700
ttctttctta taacaactct gtttccctct gaatctctat cctgttcctc tctctccatc 41760
tctgtctatg ccccattttt ctgtgcagcg tctctgcctc tctattactc attatagtcc 41820
tcacactctt atgatacttt tacaacctca ctgtcaattc agaaaatttc actgtctttg 41880
agaaaaattt aaggtatctt ctatggccca cttccacatt tctagccagg tcatatcgta 41940
gattgttagc catcatattg attcactata tttgggtacc tgcctatggt ccctgtggtg 42000
gaaaatgtgg agtgtggccc ctaaggcacc atgagccatg cacaggtcag gtccatttta 42060
tttcattcat tcatatgaaa gaggcacagc taaagtactt ttcctttgtg caatgaattc 42120
tctaaggaca ggctatatgg aatattgaat tcttgtccaa caaagatgaa gatgagatat 42180
aagaagtgtc tatgggggtg gggtccaaag atgcaagcca tggggaaaaa tttcccacgt 42240
caatgcctaa gtccaagttc tgtgttgggt ggaaaggcct gtacttcact agagattgat 42300
ccagaattat taaaaatggg tgtcctgacc cctaaacacc ctgtgaccaa gcagataacc 42360
tcatgcttta tttagtccaa cttcctacag aatctgtcat catcagaggc tgtcacattt 42420
tctgtgattt taaaaaagca tctgtgagca tatggagaag ctagtgcaaa gggcttaatt 42480
gtaaagtaac gttccatgaa atggggtctg tttttatggt gccagaacca ttttctccca 42540
gaagaactgc aattcacgaa ttatagaata ggcataggat tcatgtcccc atgtggaatg 42600
gtgactaagt gtctccagct ataaatgtct gtgctatgga agccagaaag agtaaattta 42660
aaaccatttg actctagtcg aacaaatacc atacttttcc atttccccaa atattttctc 42720
acattattgt tctatgtctt catgcaacgt ctttaatctt taaatttctt aagtgttttc 42780
ttgggtaaaa attcactcaa ctagaaaatc aaactttcta ggagtatcta gcccaagcaa 42840
taaagacttc aacatacaga agcagctcat ttctcttttt cctcctttct agatgctgta 42900
ttatgtaaaa gacatcccag ctaccctgaa attcttccat agtctcttag gtaccaatgc 42960
taagatgctc attattgttg tgtcaggtaa gttattttca ttcagcctga attttaaaac 43020
agcaataata cacgtatgca tggattcctg tgtttgaaag aagcttatat attttgtctt 43080
cattatgaaa ttcttgcctt ggcctctaat catagccaat taattttcac agtattaggg 43140
aagtcattca caacagttct caatttagaa ggtatagtgg aattaaacat ctgtctactt 43200
ctttcttttg ggaaaatatg tctttgtctt ctatatatga atccttttta tatagcttaa 43260
attcaactga caaaagattt taaatgagac taaaaatagt aaacatttat tttacctact 43320
tcgtgtcatt tgagtgtttc ttttccctct atgatgttta ttaataaata aaggttaaac 43380
tatttcagat gtcatcattt ttaattgact tgcattctta gagccatgat caacactgct 43440
tgctataggt tttttcaaat gcctatcaaa aacagttcat ttgttttgtt ttgtgttggt 43500
gttttatttt ccaaggaggc atgtgagcat gtccagttgc tgccagggat ttagtaagta 43560
tcacacagag aacccaagta aacattttta gataatgaaa cattgacatt gttgaggaca 43620
gtatttatta cttctttcat tcagcaatct ttatggattt tctaccagta cttacaggtt 43680
gattttagat acacagcaga ctctgtcttc ctaaggttac accagacccc atactttaac 43740
accgtatgtc acaaaattga cttgttctta aatatgaaga attgctttaa agatggcaag 43800
catggttata gcttgtaatc ctgggtttga ccttatgtga aagtttggca atagagagct 43860
cctgtacaca acctctcctg caagggaaca tttagatata ctatttttat ctctatttag 43920
ttaaaaatac tcatttatgt gggagaggtc tcatttccca tttagaaggg cttatggaaa 43980
ctggactcat cctactaacc tctctctgag ctagtaaagc actataaact gcatttagaa 44040
ttgcaaagta aacttagtta tcaacattgt aggcagccta ttcttgatta tattcatcaa 44100
tcatacagaa aaagtattgt agacggaaat aacaattcat tgagaagtca tgtatttttt 44160
atcttagaat atatttcatc tcaatagtag gtctaatctc ttatttatat ttggcttatt 44220
ctaacatatt ttcagaaatt aagtatctga gcacccagaa gttagctttc tataagtata 44280
tattaccaat aagacaaagc cagcctgaag tttagaaggg agcatgaata gtccacaagt 44340
aactgagaac tgattaagtg cccttatggc tacagtattc tgctggctgt atcatgaatg 44400
aattaattga tgattattgg catcaagaaa tttgaagacc aaaataaacc caatgaaatg 44460
tgttgtatgt taatacatgg tgcaagaata ctgaggcact tttaactatg tgaatttggt 44520
ctctgcatct cagtttattc aagggctatt tctggacaac cttatctgca ttatattaca 44580
tcttttcata tatgtggctc ataagtacca tctgtaaata agcattcatc ataaaaaaaa 44640
tcaaaagaaa gggagtaaag actcaacaat cagttagctt tttttgaaaa gtatttttag 44700
tcaaaaatta tttaaccaaa gtatttgatg atggaaatgt tttactcact ttctcaatat 44760
gcagttaaca attcttcatt actgcttata gcacaggaga cagctgttcc aaagaggaaa 44820
acattgttaa tagaatgcaa cgaataacat ttgacagatg attaaagaga ttctgatgat 44880
ctccttcctt taccatatca cttcttctga gaagagattt acacagctat agccatctat 44940
ttcttcctaa aagaaaaacc acttcgcaaa agtagaagaa agatttcgat attttatttg 45000
gggctttcta cgtctctctc tcctaagcct aagaatgtct tggctttttt tgcctctatt 45060
tgtcagaatg ctaagaaaat aaataaatta aatataagtt aatttttttt aaaacctact 45120
tttcccaata atgaatactt tgcagtgaaa aataattcta cctgaaaaga gaaatagaat 45180
tgtgaaatat gttgatcatt gtcatcaatt tagtagaact ggaatgtccc cagattctcc 45240
aatcctatcg gcatgtcata cttaactctt aaagatccag agtaaatgat ggagttctca 45300
tttcaagtaa cttgggtaat ccatcccctc atcatcactc ctttactcct gagggttcct 45360
gggggtcaga cttaaatgtt cctggtgatt gccatccact gtgtgctcca agttcaactt 45420
ttgatttctt ctccccaaat cttgcatgtg ctgcagccgc cctttctcat cttgtttcac 45480
attgccttaa acatggacat agtcctacct ccttccttct ccaaaacacc attcttgctt 45540
ttgacagatt ttgggacctg tgggggagaa agaggaacaa agaacagaat ttagcattaa 45600
ggtcccaccg tgactctttt tctcaccttt ctcttgctca atctggacac acttccgttg 45660
aacctgctct cataacttct ctcagtcttc cctcatatcc tcttagttca gtgctaagat 45720
gccacctcct cattttctat tgcaaccctc ttttttaact tttattttaa gttcaggggt 45780
acatctgaag gtttgtcaca taggtaaacg tgtccggggg gttgttaaac agattatttc 45840
atcacccagg tattaaaccc actacccaat aataatcttt tctgctcctc tttctccccc 45900
caccctccat cctcaagtag acctcaatgt ctgctgtttc cttctttgtg ttcatcagtt 45960
ctcatcattt agctcccact tataattgag aacatgcggt atttggtttt ctgtttctgc 46020
attagttttt taggccaata gcttctggct ccatccatgt ccccagaaaa gacatgatct 46080
ctttattttt tatggctgca tagtattcca tagtgtatat gtatcacatt ttctttaacc 46140
actctgtcac tgaagggttt ttaggttgat tccatgtctt tgctattgtg aataatcctg 46200
caatgaacat ttatgtgcat gtgtctttat gacagaatga ttaatattcc tctgggtata 46260
tacccagtaa taggtttcca aaccatacta taggggggta caataaccaa acagcatggt 46320
actggtacaa aaacaagcac atagaccaat gaaacagaat agagagacca gaaataaggc 46380
cgcacaccta cgaccatctg atctttgaca aagctgacaa aaacaagcaa tggggaaaag 46440
acttcctatt caataaatgg tggtgggata actggctagc catatgcaga agactgaagc 46500
cagtctcctt ccttatacta tatacaaaaa tcaactcaat gtggcttaaa gactacctaa 46560
aactataaaa acctggaaga caacctaggc aataccatcc tgcacatagg aacaggcaaa 46620
gattctgtga caaagacact aaaatcaata aaaacattgg caaatggcat ctcattaaac 46680
ttaagagctt ctgtacagca aaagaaacta tcaatagaat aaacagacaa cctacggaat 46740
ggtagaaaat atttgcatag tatgcatttg acaaaggtct aatatccatc atctataagg 46800
aacttaaatt tacaagagag aaacaacccc attaaaacgt gggcaaagga catgaataaa 46860
caattctcaa aagaagacag agatgtggcc aagaagcatt tgaaaaaaag ctcaacatca 46920
ctgatcatta gtgaaatgaa aatcaaaacc acaatgagat accatctcat accagtcaga 46980
atgactattt attaaaaaga caaaaaataa cagatgctga tgaggttgtg gagtaaaagg 47040
aacacataca ttgttggtga gaatgtaaag tagttcaacc actgtggaaa gcagtatggc 47100
aatttcttag agagctaaaa gcagaactac cagttgaccc agcaaccctc ttatagagta 47160
gtttaaatcc cttttgttct atttctatca cctagataaa cctgtgcaca catgaacttg 47220
tcttaacaac aacacatttc cctgagataa attgttttgc ccccctcagt gtatgatgag 47280
ggtgatggta gtttcctatt ttaaaaaaat agcaatagtt gctttgttgt attaacatac 47340
ccaatagaaa tatattggtc agcttttgga aaaatagatc aagtctagtt tccaacattg 47400
gaaacaaatt tgatcacaag aaatttccaa tcagacattt tcatattgat gtcagtgaac 47460
acacatagga atgatccaca aaattactac tcattgtttt ctttcaatga tgtagcttca 47520
aatccctatc tgctagacta gtcagtggaa agaaaacaag tttgagaaac ctcatcagcc 47580
gaggtgttcc atctacatcc ctccttaccc ctgtttagga accattgcct agcttgcctt 47640
ctccaccaga gctataattc tttaaacccc atttttcatt tactcaacag attgaaacat 47700
ttcctaaagt tgaatattga cccagaactt ggaatgtcta taccacattg gtttacacta 47760
agttctgttt ttattaagat tctttgggtc actttcttaa tggaatttgc ttcataatta 47820
cctaaaaggg aagatgcttc tgtgtatgtt catttgtttc agggtaatat tgtcatccat 47880
agctgctctc caatgcacaa aactgagtac tcatggtata tagggaggca tatagggaca 47940
ttcatctctg ttcctacatc tttgtaaaga ctttggcaca gagacaatac ttagtaaata 48000
tgttttaatt gaactgaata attgtttatt atttctgcct tatgatatca gaactacaat 48060
aagctctgaa tatacatcca aaaaaagaga atatatttca gctaaaactg acttgacgaa 48120
atcagagaac acaggaagtt ctggatattt gcagatgaag tttaataaat aggaataaaa 48180
ggctcaataa aaaagacaca cgcacacaca cacacacaca cacacacaca cacacacaca 48240
cacagcaaat ggaagcagcc agacaaaagc aataaagaac aaacaactaa aactatttgt 48300
gtatttttag ggaaagaaaa agaaattgaa atcagaatta aatgacaaca tttactggtc 48360
agcttatgga aatatatgtt gcttgatgga aatcaacctt tcctctgtgt ttctaaatat 48420
ccattacaga attaccctaa ctcaagagac tgtcatttag tgataactag tagaagttcc 48480
tgataatgga gatgaaagaa atttgatttg gggataaaaa agaagagata taagaacaag 48540
agagttggat ttctttaaaa aatgtggagt atcccacact aaaatggtat caaagaaaag 48600
tttttttctg caaatgtgat agccaagcat caattgggag ggttgctgtt taaaaggcag 48660
cctgtctggt taagggagat gagccagaag gagatcactg aagctttctg tctgtcctct 48720
ccttacctga gtaaggaagg aggaaaatca ttgtgtgtta tttttagtgc agtgagaaaa 48780
agaaaatctg gcttacatca tgttgaaaac aaaagtaaca ccatatgttg tgcccaccga 48840
gagccattat gataatgcat tagtcgggaa gtgcataatt gctcagctca gaaatggcac 48900
cgagtcacag cactgacacc agcaaatttt ttgcaattag tgtttggttc ttttttctct 48960
gccaggttaa aaataataat aatgatgata acagagcctc tcttcaacca ctgaaatgct 49020
gattttcttg taatgtcttg tttgccggca aactcttatt taggaagaca atccactgtc 49080
tttggaataa aagattttta aataaatact cacaaccctc atttattttc attgaacaga 49140
ggttttattc tttctgcttc attccaattc caccttctcc tagagcatat cctgcagtta 49200
cctctccctc ttctgaaata taagtagaac atcaattatc ctaggctatt tattatttag 49260
cctattattt gtcttggttc atctcttgag ttaaattaga tctgggaact ttagcttaat 49320
ccatgcatga gcgccaaggg tctttgagca ttctataatc ttatgcagaa ctgtgtgggt 49380
atgtattgtt tgtgtatttt tctggagagt cagttactct cactagatca taaaggggac 49440
ttgggaacca aaagtatctc aagacattta atcctagaag cacaaagaaa gtataagttg 49500
tctcttatat tgcttttgcc aaatccagtt taacacttca gtaacgttaa ctattgtgtc 49560
atggttctaa gggtctttac tttattaact cagtgaatcc ttgtagcagt ctataaatgg 49620
attatattat cacccctgtt ttacagatga taaaactgag acacaggttc ataaagttgg 49680
taagaaggaa agccaggctt catactcagg cagttgggtt ttagagacca tgctctttat 49740
tactgccctg tactgactgt gtatgtaata tgcatgtatt agaaggccca taaatagaaa 49800
ctcattatta ttattataga tttctgaata gcaggcttgc ttttttagtc tcaagaatgc 49860
aatcagtgga aatacactag caaactaatt catgtatttt ataagcactt attacacatc 49920
tttcatgtgc gtaccattac gcaataattc acttaaatta tctcatgtaa tgcttgtagt 49980
tgcattcaag gtaagtttga taatccccat tttacagatg aggaaattta agttctgaga 50040
ggctagataa caagcctcat ctcattcata aagcatcaga agaagagttc agctcatgtc 50100
tgtctccctc agataaggta ttccgtagct tctctgcagg gttagaattt cagtttagta 50160
ctacaaacat tgctaaaagg tcttctaaac ttggggacaa gatttataga aatccaccta 50220
gttattgtca gtccaaggca gcatcttttt ttatatagag atgagagtaa aaaatcattg 50280
atttgagtaa atcaccattt actgtgctct ttctttccat tttaattttc actgttaaag 50340
attcttgtct gaattccaga ctaacaacta ccttcctcat atcaccacct gaatgtccag 50400
taggtatctc aaatttatat tcctgaaacc agaggcctga tgatacaaaa ctgctcgtct 50460
tcattcttct ctccaacaat ggcaattctg tcttctcagg cgccctcaca gaaattactg 50520
gggtcatcac tgattctttc tttttaccca tatcctacat ccaaattgtt ggcgagccct 50580
gttggatctc ggagtataac acataaaaac tcccaccact tctcttcacc tcccagctca 50640
ctggtctgtg ggacccaccc ccacctatcc cccaggtgat tacagtagcc ttctcgctgt 50700
tctccccacc tctgccctta tgcgccagta ctctcttccc atcggtgagg ccagggtgac 50760
cttattaaat gtatattgag tcattctaat gtgctgttcc atacagaaac catgttttag 50820
tagtgaagtt gaaactgaaa ttaatttaaa tgaatgaaac ttaaaattca ggtcttcagt 50880
aacacttgaa actcaagtcc taagccacct ttcaagtgct ccatagcaac aagtggtgag 50940
tgacaatcct gctggacaat gcagatatcg aacgtgtcca ttggttcaga aaattctatc 51000
agacagcatt acagtggttt cccattgggc cccaagtgat ctgggccctt catccactcc 51060
ccacccctaa tctctccaac ctcatctctt ttccctctgc cctcactcat tcagctccaa 51120
tttcactggc ttcctggcta gttctttaat gggccaagta tcatcctgta ttcaggtcct 51180
ttgcagctgc tcatctctct cctggagtca tcttccccct gatatctcca tgtcttgctg 51240
tcaggtctct gctcaaatgt caggttatta gacagactct gcgaccaccc tagttaaaac 51300
agcagcccat caaagtcttt aaccctctta gcatttactc agattacttt ttcatttagc 51360
atttatcacc atatatttac ttatttttct ctctcctcct gtactccttg aaatatgagc 51420
tgcacaaagg acaagattat tattttgttc tattctaagc atctagtgta ctttctggca 51480
gactgcaaat gaaagaaaga ataaatgaaa gcatgacttg tgttttattg cacaggaagc 51540
agtggctggg acaagctgtg gaaaaagtac ggatcacgct ttccccagga tgacctctgc 51600
cagtatatca catcagatga cctcactcag atgctggaca acctagggct taagtatgag 51660
tgctatgacc ttttgtccac catggatata tctgactgct ttattgatgg taatgaaaat 51720
ggagacctgc tttgggattt tttgactgaa acctgcaact ttaatgccac agcaccacct 51780
gatctcagag cagagcttgg gaaagatcta caagagcctg aatttagtgc taagaaagag 51840
gggaaggttc tttttaataa tactctgagt ttcatagtga ttgaggcata actatcaatc 51900
acaaaagtat attcaaaaat tatattttga acaactcgaa tcactcattt atttccatat 51960
taaaatcaca aactcatcca ttaatgtaga taaagcactg tttggatatg agatgtagca 52020
aattccaata cattattgga cttccatttg gaatcatatg ggatactgct ggtcttatcc 52080
tgtccctcct ccaggtagag agaccacaag caggctcaac ataacataag ctagaaaaat 52140
tagatgactg aatttctatg gcatattgat aataaaattc attccatttg ctgattgtct 52200
gaaattttct agaatactaa taaaatacat actatagatt ctttattagt gaagtatgca 52260
ctaatcaata ctttgaacac aaagcctgtg ttactgattt ggccgttttg tgaagaaaca 52320
tttatctttg tacgttcttc tattgtgctt tctatctaat ttttattaat ttgtaagagt 52380
aagcaccttt agaatattaa aaattaattc tttatcacat gttgtca 52427
<210>2
<211>20
<212>DNA
<213>智人(Homo sapiens)
<400>2
atatttgaca gcaggcaagg 20
<210>3
<211>20
<212>DNA
<213>智人(Homo sapiens)
<400>3
ccgggggaaa gtgtaatatc 20
<210>4
<211>20
<212>DNA
<213>智人(Homo sapiens)
<400>4
gtttcagcca aagtcagaca 20
<210>5
<211>20
<212>DNA
<213>智人(Homo sapiens)
<400>5
ctgccctcta agcattcaaa 20
<210>6
<211>20
<212>DNA
<213>智人(Homo sapiens)
<400>6
aggttgcagt gagtggagat 20
<210>7
<211>20
<212>DNA
<213>智人(Homo sapiens)
<400>7
gaagctgcat ttaggggaat 20
<210>8
<211>20
<212>DNA
<213>智人(Homo sapiens)
<400>8
tgcactttta ccctggtgtc 20
<210>9
<211>20
<212>DNA
<213>智人(Homo sapiens)
<400>9
gcaaggctgt aaatccactg 20
<210>10
<211>20
<212>DNA
<213>智人(Homo sapiens)
<400>10
tgcaaagtcc cgttcaaata 20
<210>11
<211>20
<212>DNA
<213>智人(Homo sapiens)
<400>11
taattcgccc ttatccctgt 20
<210>12
<211>20
<212>DNA
<213>智人(Homo sapiens)
<400>12
actgccattt ccaagtctcc 20
<210>13
<211>20
<212>DNA
<213>智人(Homo sapiens)
<400>13
cgatctcttc caaaagcaaa 20
<210>14
<211>20
<212>DNA
<213>智人(Homo sapiens)
<400>14
agggcagcag ttgaacatta 20
<210>15
<211>20
<212>DNA
<213>智人(Homo sapiens)
<400>15
gtttagtcat gcctgccaag 20
<210>16
<211>21
<212>DNA
<213>智人(Homo sapiens)
<400>16
tctggtctcc cagacataag a 21
<210>17
<211>20
<212>DNA
<213>智人(Homo sapiens)
<400>17
ggcagatcat ggtcacttgt 20
<210>18
<211>20
<212>DNA
<213>智人(Homo sapiens)
<400>18
tgctatggaa gccagaaaga 20
<210>19
<211>20
<212>DNA
<213>智人(Homo sapiens)
<400>19
gccaaggcaa gaatttcata 20
<210>20
<211>20
<212>DNA
<213>智人(Homo sapiens)
<400>20
tatgagctgc acaaaggaca 20
<210>21
<211>20
<212>DNA
<213>智人(Homo sapiens)
<400>21
ccttcccctc tttcttagca 20
<210>22
<211>20
<212>DNA
<213>智人(Homo sapiens)
<400>22
actttaatgc cacagcacca 20
<210>23
<211>20
<212>DNA
<213>智人(Homo sapiens)
<400>23
tcagacaatc agcaaatgga 20
Claims (8)
1.一种体外对个体的高血压易感性进行辅助性诊断的方法,其特征在于,它包括步骤:
检测该个体的组胺N-甲基转移酶HNMT基因的基因组序列并与正常的HNMT基因的基因组序列相比较,
存在差异就表明该个体患高血压的可能性高于正常人群,
其中所述的差异是在HNMT的基因组序列的第616、7798、40000、51951、和52109位,存在选自下组的单倍型:
(i)TAGAA
(ii)TGAGT,
其中,核苷酸位置编号基于SEQ ID NO:1。
2.如权利要求1所述的方法,其特征在于,检测的HNMT基因组序列来自于个体细胞的DNA抽提物。
3.如权利要求1所述的方法,其特征在于,所述的细胞是外周血白细胞。
4.一种检测样品是否存在HNMT基因的单倍型的方法,其特征在于,包括步骤:
(a)用HNMT基因特异性引物扩增样品的HNMT基因,得到扩增产物;和
(b)检测扩增产物中对应于HNMT的基因组序列的第616、7798、40000、51951、和52109位的核苷酸,并判断是否存在选自下组的单倍型:
(i)TAGAA;
(ii)TGAGT;
(iii)TGAAA;
(iv)CAAAA
其中,核苷酸位置编号基于SEQ ID NO:1。
5.如权利要求4所述的方法,其特征在于,所述的单倍型是(i)TAGAA;或(ii)TGAGT。
6.一种用于辅助性检测高血压的试剂盒,其特征在于,它包括特异性扩增HNMT基因的引物和说明书,所述的引物所扩增出的扩增产物含有对应于HNMT的基因组序列的第616、7798、40000、51951、和52109位的核苷酸,其中,核苷酸位置编号基于SEQ ID NO:1。
7.如权利要求6所述的试剂盒,其特征在于,它还含有与第616、7798、40000、51951、和52109位的部位结合的探针。
8.一种组胺N-甲基转移酶的cDNA序列或基因组序列的用途,其特征在于,用于制备检测原发性高血压的试剂。
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