严重急性呼吸综合征冠状病毒1型

严重急性呼吸综合症冠状病毒1型
	SARS病毒的电子显微镜图片
病毒分类
（未分级）：	病毒 Virus
域：	核糖病毒域 Riboviria
界：	正核糖病毒界 Orthornavirae
门：	小核糖病毒门 Pisuviricota
纲：	小南嵌套病毒纲 Pisoniviricetes
目：	套式病毒目 Nidovirales
科：	冠状病毒科 Coronaviridae
属：	乙型冠状病毒属 Betacoronavirus
亚属：	SARS乙型冠状病毒亚属 Sarbecovirus
种：	严重急性呼吸综合征相关冠状病毒 ; Severe acute respiratory syndrome-related coronavirus
毒株：	严重急性呼吸综合症冠状病毒1型 ; Severe acute respiratory syndrome coronavirus
异名
	SARS coronavirus; Severe acute respiratory syndrome coronavirus;

严重急性呼吸综合征冠状病毒1型^[2]（英语：Severe acute respiratory syndrome coronavirus 1，SARS-CoV-1），简称SARS冠状病毒或SARS病毒，旧称严重急性呼吸综合征冠状病毒（英语：Severe acute respiratory syndrome coronavirus ，SARS-CoV），是冠状病毒科乙型冠状病毒属严重急性呼吸综合征相关冠状病毒种的一个分型，可引发严重急性呼吸综合征（SARS）^[3]。2003年4月16日，世界卫生组织发布新闻稿，确认SARS冠状病毒是SARS的病原体。纽约、旧金山、马尼拉，香港和多伦多的实验室存放了SARS冠状病毒的标本。

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2003年4月，美国疾病控制与预防中心和加拿大国家微生物学实验室（英语：National Microbiology Laboratory）识别了SARS冠状病毒的基因^[4]^[5]。伊拉斯姆斯大学的研究者证实，SARS冠状病毒满足科赫法则，因此可以确认是SARS的病原体。实验中，感染该疾病的猕猴表现出和人类相同的症状^[6]。

2019冠状病毒疾病有很多和SARS相似的病症，这种疾病的病原体被认为是严重急性呼吸综合征相关冠状病毒的另一个分型，称为严重急性呼吸综合征冠状病毒2（SARS-CoV-2）。尽管SARS冠状病毒和SARS-CoV-2被分类为同一个物种，SARS-CoV-2不是SARS冠状病毒的直接后代，而是分别传播给人类的。

疾病

SARS是SARS冠状病毒引起的严重疾病，通常以肌肉疼痛、头痛和发烧等全身症状为特征，并于2-14天内出现咳嗽、呼吸困难和肺炎等呼吸道症状^[7]。SARS患者血液中循环的淋巴细胞数量也常常会减少^[8]。

2003年的SARS事件中，SARS冠状病毒感染的确诊患者中有9%死亡^[9]。60岁以上人群死亡率更高，接近50％^[9]。

历史

2003年4月12日，温哥华迈克尔·史密斯基因组科学中心的研究者完成了SARS冠状病毒基因序列的绘制。^[10]此后，其它课题组也确认了SARS冠状病毒的序列。2003年5月底，研究者调查了在广东市场上作为食品出售的野生动物样本，并从果子狸的样本中分离出了SARS冠状病毒，但这些动物并不总能显示出临床体征。初步结论是，SARS病毒越过了物种屏障，从果子狸传播到人类。广东省1万多只果子狸被捕杀。之后，鼬獾、貉和家猫也被发现是SARS病毒的宿主。2005年，两项研究调查了中国蝙蝠携带的SARS类似冠状病毒^[11]^[12]，这些病毒的系统发育分析表明，SARS冠状病毒很可能起源于蝙蝠，并直接传播给人类，或通过中国市场上的动物传播给人类。蝙蝠未显示任何明显的疾病迹象，但可能是SARS类似冠状病毒的天然宿主。2006年底，研究者建立了鼠类和人类中出现的SARS冠状病毒之间的遗传联系，并认为SARS已完成跨物种跳跃^[13]。2017年，石正丽等人的研究发现，SARS病毒可能起源于云南菊头蝠携带的SARS相关冠状病毒^[14]。

病毒学

SARS冠状病毒具有冠状病毒科典型的复制策略。2003年的研究表明，SARS冠状病毒主要的人类受体是血管紧张素转化酶2（ACE2）^[15]。

演化树

截至2021年1月 (2021-01)^[update]，SARS-CoV与相关病毒株的系统发生树：

16BO133 与SARS-COV相似度82.8 % · 马铁菊头蝠 · 韩国全罗北道（2016年采集、2019年发表）^[16]

	Rf1 87.8 % · 马铁菊头蝠 · 中国湖北宜昌（2004年采集、2005年发表）^[17]

	BtCoV HKU3 87.9 % · 中华菊头蝠 · 香港、中国广东（2004年采集、2005年发表、2010年又发表若干新病毒株）^[18]

LYRa11 90.9 % · 中菊头蝠 · 中国云南保山（2011年采集、2014年发表）^[19]

Rp3 92.6 % · 皮氏菊头蝠 · 中国广西南宁（2004年采集、2005年发表）^[17]

	SL-CoV YNLF_31C 93.5 % · 马铁菊头蝠 · 中国云南禄丰（2013年采集、2015年发表）^[20]

	SL-CoV YNLF_34C 93.5 % · 马铁菊头蝠 · 中国云南禄丰（2013年采集、2015年发表）^[20]

	SHC014 95.4 % · 中华菊头蝠 · 中国云南昆明（2011年采集、2013年发表）^[21]

	WIV1 95.6 % · 中华菊头蝠 · 中国云南昆明（2012年采集、2013年发表）^[21]

WIV16 96.0 % · 中华菊头蝠 · 中国云南昆明（2013年采集、2016年发表）^[22]

	果子狸SARS冠状病毒 99.8 % · 果子狸 · 中国广东^[18]

	SARS-CoV 100 %

SARS-CoV-2 79 %

蝙蝠病毒

果子狸病毒

人类病毒

参考文献

引用

[1]
ICTV Taxonomy history: Severe acute respiratory syndrome-related coronavirus. International Committee on Taxonomy of Viruses (ICTV). [2019-01-27]. （原始内容 (html)存档于2020-02-22）（英语）.
[2]
新冠肺炎 (COVID-19) 的免疫學探討 (PDF). 台湾医界. 2020 [2022-12-27]. （原始内容存档 (PDF)于2022-12-27）.
[3]
Thiel V (editor). Coronaviruses: Molecular and Cellular Biology 1st. Caister Academic Press. 2007. ISBN 978-1-904455-16-5.
[4]
Remembering SARS: A Deadly Puzzle and the Efforts to Solve It. Centers for Disease Control and Prevention. 2013-04-11 [2013-08-03]. （原始内容存档于2013-08-01）.
[5]
Coronavirus never before seen in humans is the cause of SARS. United Nations World Health Organization. 2006-04-16 [2006-07-05]. （原始内容存档于2004-08-12）.
[6]
Fouchier RA, Kuiken T, Schutten M, et al. Aetiology: Koch's postulates fulfilled for SARS virus. Nature. 2003, 423 (6937): 240. Bibcode:2003Natur.423..240F. PMID 12748632. doi:10.1038/423240a.
[7]
Chan-Yeung M; Xu RH. SARS: epidemiology. Respirology (Carlton, Vic.). November 2003, 8 (Suppl): S9–14. PMID 15018127. doi:10.1046/j.1440-1843.2003.00518.x.
[8]
Yang M; Li CK; Li K; Hon KL; Ng MH; Chan PK; Fok TF. Hematological findings in SARS patients and possible mechanisms (review). International Journal of Molecular Medicine. August 2004, 14 (2): 311–5 [2020-02-17]. PMID 15254784. doi:10.3892/ijmm.14.2.311. （原始内容存档于2015-09-24）.
[9]
Sørensen MD; Sørensen B; Gonzalez-Dosal R; Melchjorsen CJ; Weibel J; Wang SARS-CoVJ; Jun CW; Huanming Y; Kristensen P. Severe acute respiratory syndrome (SARS): development of diagnostics and antivirals. Annals of the New York Academy of Sciences. May 2006, 1067 (1): 500–5. Bibcode:2006NYASA1067..500S. PMID 16804033. doi:10.1196/annals.1354.072.
[10]
B.C. lab cracks suspected SARS code. CBCNews, Canada. April 2003 [2020-02-17]. （原始内容存档于2007-11-26）.
[11]
Li W, Shi Z, Yu M, et al. Bats are natural reservoirs of SARS-like coronaviruses. Science. 2005, 310 (5748): 676–9. Bibcode:2005Sci...310..676L. PMID 16195424. doi:10.1126/science.1118391.
[12]
Lau SK, Woo PC, Li KS, et al. Severe acute respiratory syndrome coronavirus-like virus in Chinese horseshoe bats. Proc. Natl. Acad. Sci. U.S.A. 2005, 102 (39): 14040–5. Bibcode:2005PNAS..10214040L. PMC 1236580 . PMID 16169905. doi:10.1073/pnas.0506735102.
[13]
Scientists prove SARS-civet cat link. China Daily. 2006-11-23 [2020-02-17]. （原始内容存档于2011-06-14）.
[14]
Hu, Ben; Zeng, Lei-Ping; Yang, Xing-Lou; Ge, Xing-Yi; Zhang, Wei; Li, Bei; Xie, Jia-Zheng; Shen, Xu-Rui; Zhang, Yun-Zhi. Drosten, Christian , 编. Discovery of a rich gene pool of bat SARS-related coronaviruses provides new insights into the origin of SARS coronavirus. PLOS Pathogens. 2017-11-30, 13 (11): e1006698 [2020-02-20]. ISSN 1553-7374. PMC 5708621 . PMID 29190287. doi:10.1371/journal.ppat.1006698. （原始内容存档于2020-07-31）（英语）.
[15]
Li, Wenhui; Moore, Michael J.; Vasilieva, Natalya; Sui, Jianhua; Wong, Swee Kee; Berne, Michael A.; Somasundaran, Mohan; Sullivan, John L.; Luzuriaga, Katherine. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature. 2003-11, 426 (6965): 450–454 [2020-02-20]. ISSN 0028-0836. doi:10.1038/nature02145. （原始内容存档于2020-12-09）（英语）.
[16]
Kim, Yongkwan; Son, Kidong; Kim, Young-Sik; Lee, Sook-Young; Jheong, Weonhwa; Oem, Jae-Ku. Complete genome analysis of a SARS-like bat coronavirus identified in the Republic of Korea. Virus Genes. 2019-08, 55 (4). ISSN 0920-8569. PMC 7089380 . PMID 31076983. doi:10.1007/s11262-019-01668-w （英语）.
[17]
Li, Wendong; Shi, Zhengli; Yu, Meng; Ren, Wuze; Smith, Craig; Epstein, Jonathan H.; Wang, Hanzhong; Crameri, Gary; Hu, Zhihong; Zhang, Huajun; Zhang, Jianhong. Bats Are Natural Reservoirs of SARS-Like Coronaviruses. Science. 2005-10-28, 310 (5748). ISSN 0036-8075. doi:10.1126/science.1118391 （英语）.
[18]
Ge, Xing-Yi; Hu, Ben; Shi, Zheng-Li. Bat Coronaviruses. Wang, Lin-Fa (编). Bats and Viruses. Hoboken, NJ: John Wiley & Sons, Inc. 2015-06-26: 127–155. ISBN 978-1-118-81882-4. doi:10.1002/9781118818824.ch5 （英语）.
[19]
He, Biao; Zhang, Yuzhen; Xu, Lin; Yang, Weihong; Yang, Fanli; Feng, Yun; Xia, Lele; Zhou, Jihua; Zhen, Weibin; Feng, Ye; Guo, Huancheng. Perlman, S. , 编. Identification of Diverse Alphacoronaviruses and Genomic Characterization of a Novel Severe Acute Respiratory Syndrome-Like Coronavirus from Bats in China. Journal of Virology. 2014-06-15, 88 (12). ISSN 0022-538X. PMC 4054348 . PMID 24719429. doi:10.1128/JVI.00631-14 （英语）.
[20]
Lau, Susanna K. P.; Feng, Yun; Chen, Honglin; Luk, Hayes K. H.; Yang, Wei-Hong; Li, Kenneth S. M.; Zhang, Yu-Zhen; Huang, Yi; Song, Zhi-Zhong; Chow, Wang-Ngai; Fan, Rachel Y. Y. Perlman, S. , 编. Severe Acute Respiratory Syndrome (SARS) Coronavirus ORF8 Protein Is Acquired from SARS-Related Coronavirus from Greater Horseshoe Bats through Recombination. Journal of Virology. 2015-10-15, 89 (20). ISSN 0022-538X. PMC 4580176 . PMID 26269185. doi:10.1128/JVI.01048-15 （英语）.
[21]
Ge, Xing-Yi; Li, Jia-Lu; Yang, Xing-Lou; Chmura, Aleksei A.; Zhu, Guangjian; Epstein, Jonathan H.; Mazet, Jonna K.; Hu, Ben; Zhang, Wei; Peng, Cheng; Zhang, Yu-Ji. Isolation and characterization of a bat SARS-like coronavirus that uses the ACE2 receptor. Nature. 2013-11, 503 (7477). Bibcode:2013Natur.503..535G. ISSN 0028-0836. PMC 5389864 . PMID 24172901. doi:10.1038/nature12711 （英语）.
[22]
Yang, Xing-Lou; Hu, Ben; Wang, Bo; Wang, Mei-Niang; Zhang, Qian; Zhang, Wei; Wu, Li-Jun; Ge, Xing-Yi; Zhang, Yun-Zhi; Daszak, Peter; Wang, Lin-Fa. Perlman, S. , 编. Isolation and Characterization of a Novel Bat Coronavirus Closely Related to the Direct Progenitor of Severe Acute Respiratory Syndrome Coronavirus. Journal of Virology. 2016-03-15, 90 (6). ISSN 0022-538X. PMC 4810638 . PMID 26719272. doi:10.1128/JVI.02582-15 （英语）.

来源

Peiris JS, Lai ST, Poon LL, et al. Coronavirus as a possible cause of severe acute respiratory syndrome. Lancet. April 2003, 361 (9366): 1319–25. PMID 12711465. doi:10.1016/s0140-6736(03)13077-2.
Rota, P. A. Characterization of a Novel Coronavirus Associated with Severe Acute Respiratory Syndrome. Science. 2003-05-30, 300 (5624): 1394–1399. doi:10.1126/science.1085952.
Marra, M. A. The Genome Sequence of the SARS-Associated Coronavirus. Science. 2003-05-30, 300 (5624): 1399–1404. doi:10.1126/science.1085953.
Snijder, Eric J.; Bredenbeek, Peter J.; Dobbe, Jessika C.; Thiel, Volker; Ziebuhr, John; Poon, Leo L.M.; Guan, Yi; Rozanov, Mikhail; Spaan, Willy J.M. Unique and Conserved Features of Genome and Proteome of SARS-coronavirus, an Early Split-off From the Coronavirus Group 2 Lineage. Journal of Molecular Biology. 2003-08, 331 (5): 991–1004 [2020-02-20]. doi:10.1016/S0022-2836(03)00865-9. （原始内容存档于2020-10-19）（英语）.
Yount B, et al. Rewiring the severe acute respiratory syndrome coronavirus (SARS冠状病毒) transcription circuit: engineering a recombination-resistant genome. Proc Natl Acad Sci U S A. 2006-08-15, 103 (33): 12546–51 [2020-02-05]. Bibcode:2006PNAS..10312546Y. PMC 1531645 . PMID 16891412. doi:10.1073/pnas.0605438103. （原始内容存档于2012-10-29）.
Thiel V (编). Coronaviruses: Molecular and Cellular Biology 1st. Caister Academic Press. 2007. ISBN 978-1-904455-16-5.
Enjuanes L, et al. Coronavirus Replication and Interaction with Host. Animal Viruses: Molecular Biology. Caister Academic Press. 2008. ISBN 978-1-904455-22-6.

外部链接

维基物种上的相关信息：严重急性呼吸综合症冠状病毒1型

参见

[TaxHist-1] [1]
ICTV Taxonomy history: Severe acute respiratory syndrome-related coronavirus. International Committee on Taxonomy of Viruses (ICTV). [2019-01-27]. （原始内容 (html)存档于2020-02-22）（英语）.

[2] [2]
新冠肺炎 (COVID-19) 的免疫學探討 (PDF). 台湾医界. 2020 [2022-12-27]. （原始内容存档 (PDF)于2022-12-27）.

[Thiel-3] [3]
Thiel V (editor). Coronaviruses: Molecular and Cellular Biology 1st. Caister Academic Press. 2007. ISBN 978-1-904455-16-5.

[4] [4]
Remembering SARS: A Deadly Puzzle and the Efforts to Solve It. Centers for Disease Control and Prevention. 2013-04-11 [2013-08-03]. （原始内容存档于2013-08-01）.

[5] [5]
Coronavirus never before seen in humans is the cause of SARS. United Nations World Health Organization. 2006-04-16 [2006-07-05]. （原始内容存档于2004-08-12）.

[6] [6]
Fouchier RA, Kuiken T, Schutten M, et al. Aetiology: Koch's postulates fulfilled for SARS virus. Nature. 2003, 423 (6937): 240. Bibcode:2003Natur.423..240F. PMID 12748632. doi:10.1038/423240a.

[pmid15018127-7] [7]
Chan-Yeung M; Xu RH. SARS: epidemiology. Respirology (Carlton, Vic.). November 2003, 8 (Suppl): S9–14. PMID 15018127. doi:10.1046/j.1440-1843.2003.00518.x.

[pmid15254784-8] [8]
Yang M; Li CK; Li K; Hon KL; Ng MH; Chan PK; Fok TF. Hematological findings in SARS patients and possible mechanisms (review). International Journal of Molecular Medicine. August 2004, 14 (2): 311–5 [2020-02-17]. PMID 15254784. doi:10.3892/ijmm.14.2.311. （原始内容存档于2015-09-24）.

[pmid16804033-9] [9]
Sørensen MD; Sørensen B; Gonzalez-Dosal R; Melchjorsen CJ; Weibel J; Wang SARS-CoVJ; Jun CW; Huanming Y; Kristensen P. Severe acute respiratory syndrome (SARS): development of diagnostics and antivirals. Annals of the New York Academy of Sciences. May 2006, 1067 (1): 500–5. Bibcode:2006NYASA1067..500S. PMID 16804033. doi:10.1196/annals.1354.072.

[10] [10]
B.C. lab cracks suspected SARS code. CBCNews, Canada. April 2003 [2020-02-17]. （原始内容存档于2007-11-26）.

[Li-11] [11]
Li W, Shi Z, Yu M, et al. Bats are natural reservoirs of SARS-like coronaviruses. Science. 2005, 310 (5748): 676–9. Bibcode:2005Sci...310..676L. PMID 16195424. doi:10.1126/science.1118391.

[Lau-12] [12]
Lau SK, Woo PC, Li KS, et al. Severe acute respiratory syndrome coronavirus-like virus in Chinese horseshoe bats. Proc. Natl. Acad. Sci. U.S.A. 2005, 102 (39): 14040–5. Bibcode:2005PNAS..10214040L. PMC 1236580 . PMID 16169905. doi:10.1073/pnas.0506735102.

[13] [13]
Scientists prove SARS-civet cat link. China Daily. 2006-11-23 [2020-02-17]. （原始内容存档于2011-06-14）.

[14] [14]
Hu, Ben; Zeng, Lei-Ping; Yang, Xing-Lou; Ge, Xing-Yi; Zhang, Wei; Li, Bei; Xie, Jia-Zheng; Shen, Xu-Rui; Zhang, Yun-Zhi. Drosten, Christian , 编. Discovery of a rich gene pool of bat SARS-related coronaviruses provides new insights into the origin of SARS coronavirus. PLOS Pathogens. 2017-11-30, 13 (11): e1006698 [2020-02-20]. ISSN 1553-7374. PMC 5708621 . PMID 29190287. doi:10.1371/journal.ppat.1006698. （原始内容存档于2020-07-31）（英语）.

[15] [15]
Li, Wenhui; Moore, Michael J.; Vasilieva, Natalya; Sui, Jianhua; Wong, Swee Kee; Berne, Michael A.; Somasundaran, Mohan; Sullivan, John L.; Luzuriaga, Katherine. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature. 2003-11, 426 (6965): 450–454 [2020-02-20]. ISSN 0028-0836. doi:10.1038/nature02145. （原始内容存档于2020-12-09）（英语）.

[pmid31076983-16] [16]
Kim, Yongkwan; Son, Kidong; Kim, Young-Sik; Lee, Sook-Young; Jheong, Weonhwa; Oem, Jae-Ku. Complete genome analysis of a SARS-like bat coronavirus identified in the Republic of Korea. Virus Genes. 2019-08, 55 (4). ISSN 0920-8569. PMC 7089380 . PMID 31076983. doi:10.1007/s11262-019-01668-w （英语）.

[Li2005-17] [17]
Li, Wendong; Shi, Zhengli; Yu, Meng; Ren, Wuze; Smith, Craig; Epstein, Jonathan H.; Wang, Hanzhong; Crameri, Gary; Hu, Zhihong; Zhang, Huajun; Zhang, Jianhong. Bats Are Natural Reservoirs of SARS-Like Coronaviruses. Science. 2005-10-28, 310 (5748). ISSN 0036-8075. doi:10.1126/science.1118391 （英语）.

[book2015-18] [18]
Ge, Xing-Yi; Hu, Ben; Shi, Zheng-Li. Bat Coronaviruses. Wang, Lin-Fa (编). Bats and Viruses. Hoboken, NJ: John Wiley & Sons, Inc. 2015-06-26: 127–155. ISBN 978-1-118-81882-4. doi:10.1002/9781118818824.ch5 （英语）.

[pmid24719429-19] [19]
He, Biao; Zhang, Yuzhen; Xu, Lin; Yang, Weihong; Yang, Fanli; Feng, Yun; Xia, Lele; Zhou, Jihua; Zhen, Weibin; Feng, Ye; Guo, Huancheng. Perlman, S. , 编. Identification of Diverse Alphacoronaviruses and Genomic Characterization of a Novel Severe Acute Respiratory Syndrome-Like Coronavirus from Bats in China. Journal of Virology. 2014-06-15, 88 (12). ISSN 0022-538X. PMC 4054348 . PMID 24719429. doi:10.1128/JVI.00631-14 （英语）.

[LauFeng2015-20] [20]
Lau, Susanna K. P.; Feng, Yun; Chen, Honglin; Luk, Hayes K. H.; Yang, Wei-Hong; Li, Kenneth S. M.; Zhang, Yu-Zhen; Huang, Yi; Song, Zhi-Zhong; Chow, Wang-Ngai; Fan, Rachel Y. Y. Perlman, S. , 编. Severe Acute Respiratory Syndrome (SARS) Coronavirus ORF8 Protein Is Acquired from SARS-Related Coronavirus from Greater Horseshoe Bats through Recombination. Journal of Virology. 2015-10-15, 89 (20). ISSN 0022-538X. PMC 4580176 . PMID 26269185. doi:10.1128/JVI.01048-15 （英语）.

[2013Nature-21] [21]
Ge, Xing-Yi; Li, Jia-Lu; Yang, Xing-Lou; Chmura, Aleksei A.; Zhu, Guangjian; Epstein, Jonathan H.; Mazet, Jonna K.; Hu, Ben; Zhang, Wei; Peng, Cheng; Zhang, Yu-Ji. Isolation and characterization of a bat SARS-like coronavirus that uses the ACE2 receptor. Nature. 2013-11, 503 (7477). Bibcode:2013Natur.503..535G. ISSN 0028-0836. PMC 5389864 . PMID 24172901. doi:10.1038/nature12711 （英语）.

[pmid26719272-22] [22]
Yang, Xing-Lou; Hu, Ben; Wang, Bo; Wang, Mei-Niang; Zhang, Qian; Zhang, Wei; Wu, Li-Jun; Ge, Xing-Yi; Zhang, Yun-Zhi; Daszak, Peter; Wang, Lin-Fa. Perlman, S. , 编. Isolation and Characterization of a Novel Bat Coronavirus Closely Related to the Direct Progenitor of Severe Acute Respiratory Syndrome Coronavirus. Journal of Virology. 2016-03-15, 90 (6). ISSN 0022-538X. PMC 4810638 . PMID 26719272. doi:10.1128/JVI.02582-15 （英语）.

[2]

[3]

[1]

[4]

[5]

[6]

[7]

[8]

[9]

[10]

[11]

[12]

[13]

[14]

[15]

[16]

[17]

[18]

[19]

[20]

[21]

[22]