{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T14:10:42Z","timestamp":1770991842017,"version":"3.50.1"},"reference-count":51,"publisher":"Elsevier BV","issue":"3","license":[{"start":{"date-parts":[[2021,8,1]],"date-time":"2021-08-01T00:00:00Z","timestamp":1627776000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2021,8,1]],"date-time":"2021-08-01T00:00:00Z","timestamp":1627776000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"}],"funder":[{"DOI":"10.13039\/100002603","name":"American Society for Reproductive Medicine Birmingham","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100002603","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["fertstertscience.org","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["F&S Science"],"published-print":{"date-parts":[[2021,8]]},"DOI":"10.1016\/j.xfss.2021.07.002","type":"journal-article","created":{"date-parts":[[2021,7,20]],"date-time":"2021-07-20T06:14:14Z","timestamp":1626761654000},"page":"237-247","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":6,"title":["Exogenous insulin-like growth factor 1 accelerates growth and maturation of follicles in human cortical xenografts and increases ovarian output in mice"],"prefix":"10.1016","volume":"2","author":[{"given":"Limor","family":"Man","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicole","family":"Lustgarten Guahmich","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6666-4016","authenticated-orcid":false,"given":"Eleni","family":"Kallinos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Park","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Barbara","family":"Caiazza","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monica","family":"Khan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zong-Ying","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ritaben","family":"Patel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carmen","family":"Torres","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jovana","family":"Lekovich","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liangwen","family":"Zhong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard","family":"Bodine","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3160-6289","authenticated-orcid":false,"given":"Duancheng","family":"Wen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nikica","family":"Zaninovic","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Glenn","family":"Schattman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zev","family":"Rosenwaks","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0975-2554","authenticated-orcid":false,"given":"Daylon","family":"James","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"78","reference":[{"key":"10.1016\/j.xfss.2021.07.002_bib1","first-page":"825","article-title":"A hormonally controlled serum factor which stimulates sulfate incorporation by cartilage in\u00a0vitro","volume":"49","author":"Salmon","year":"1957","journal-title":"J Lab Clin Med"},{"key":"10.1016\/j.xfss.2021.07.002_bib2","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1038\/235107a0","article-title":"Somatomedin: proposed designation for sulphation factor","volume":"235","author":"Daughaday","year":"1972","journal-title":"Nature"},{"key":"10.1016\/j.xfss.2021.07.002_bib3","doi-asserted-by":"crossref","first-page":"2365","DOI":"10.1073\/pnas.73.7.2365","article-title":"Polypeptides with nonsuppressible insulin-like and cell-growth promoting activities in human serum: isolation, chemical characterization, and some biological properties of forms I and II","volume":"73","author":"Rinderknecht","year":"1976","journal-title":"Proc Natl Acad Sci U S A"},{"key":"10.1016\/j.xfss.2021.07.002_bib4","doi-asserted-by":"crossref","first-page":"T69","DOI":"10.1530\/JME-17-0311","article-title":"IGF1 receptor signaling pathways","volume":"61","author":"Hakuno","year":"2018","journal-title":"J Mol Endocrinol"},{"key":"10.1016\/j.xfss.2021.07.002_bib5","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1038\/35041700","article-title":"Genetic pathways that regulate ageing in model organisms","volume":"408","author":"Guarente","year":"2000","journal-title":"Nature"},{"key":"10.1016\/j.xfss.2021.07.002_bib6","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1126\/science.1057987","article-title":"A mutant Drosophila insulin receptor homolog that extends life-span and impairs neuroendocrine function","volume":"292","author":"Tatar","year":"2001","journal-title":"Science"},{"key":"10.1016\/j.xfss.2021.07.002_bib7","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1038\/nature01298","article-title":"IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice","volume":"421","author":"Holzenberger","year":"2003","journal-title":"Nature"},{"key":"10.1016\/j.xfss.2021.07.002_bib8","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.3001845","article-title":"Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans","volume":"3","author":"Guevara-Aguirre","year":"2011","journal-title":"Sci Transl Med"},{"key":"10.1016\/j.xfss.2021.07.002_bib9","doi-asserted-by":"crossref","first-page":"3438","DOI":"10.1073\/pnas.0705467105","article-title":"Functionally significant insulin-like growth factor I receptor mutations in centenarians","volume":"105","author":"Suh","year":"2008","journal-title":"Proc Natl Acad Sci U S A"},{"key":"10.1016\/j.xfss.2021.07.002_bib10","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1111\/acel.12213","article-title":"Low insulin-like growth factor-1 level predicts survival in humans with exceptional longevity","volume":"13","author":"Milman","year":"2014","journal-title":"Aging Cell"},{"key":"10.1016\/j.xfss.2021.07.002_bib11","first-page":"4667","article-title":"Dietary restriction reduces insulin-like growth factor I levels, which modulates apoptosis, cell proliferation, and tumor progression in p53-deficient mice","volume":"57","author":"Dunn","year":"1997","journal-title":"Cancer Res"},{"key":"10.1016\/j.xfss.2021.07.002_bib12","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1111\/j.1474-9726.2008.00417.x","article-title":"Long-term effects of calorie or protein restriction on serum IGF-1 and IGFBP-3 concentration in humans","volume":"7","author":"Fontana","year":"2008","journal-title":"Aging Cell"},{"key":"10.1016\/j.xfss.2021.07.002_bib13","doi-asserted-by":"crossref","first-page":"3557","DOI":"10.1038\/ncomms4557","article-title":"Caloric restriction reduces age-related and all-cause mortality in rhesus monkeys","volume":"5","author":"Colman","year":"2014","journal-title":"Nat Commun"},{"key":"10.1016\/j.xfss.2021.07.002_bib14","first-page":"903","article-title":"Effects of an Igf1 gene null mutation on mouse reproduction","volume":"10","author":"Baker","year":"1996","journal-title":"Mol Endocrinol"},{"key":"10.1016\/j.xfss.2021.07.002_bib15","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1159\/000184193","article-title":"Laron syndrome: clinical features, molecular pathology and treatment","volume":"42","author":"Laron","year":"1994","journal-title":"Horm Res"},{"key":"10.1016\/j.xfss.2021.07.002_bib16","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1080\/03014469100001452","article-title":"The comparative growth of Efe pygmies and African farmers from birth to age 5 years","volume":"18","author":"Bailey","year":"1991","journal-title":"Ann Hum Biol"},{"key":"10.1016\/j.xfss.2021.07.002_bib17","doi-asserted-by":"crossref","first-page":"3732","DOI":"10.1210\/jcem.80.12.8530626","article-title":"Insulin-like growth factor I resistance in immortalized T cell lines from African Efe Pygmies","volume":"80","author":"Geffner","year":"1995","journal-title":"J Clin Endocrinol Metab"},{"key":"10.1016\/j.xfss.2021.07.002_bib18","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1093\/molehr\/6.2.137","article-title":"Expression of receptors for insulin-like growth factor-I and transforming growth factor-beta in human follicles","volume":"6","author":"Qu","year":"2000","journal-title":"Mol Hum Reprod"},{"key":"10.1016\/j.xfss.2021.07.002_bib19","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1093\/humrep\/13.2.285","article-title":"Insulin-like growth factor (IGF)-I and IGF binding protein-3 concentrations in fluid from human stimulated follicles","volume":"13","author":"Oosterhuis","year":"1998","journal-title":"Hum Reprod"},{"key":"10.1016\/j.xfss.2021.07.002_bib20","doi-asserted-by":"crossref","first-page":"2309","DOI":"10.1210\/en.2017-00146","article-title":"IGF1R expression in ovarian granulosa cells is essential for steroidogenesis, follicle survival, and fertility in female mice","volume":"158","author":"Baumgarten","year":"2017","journal-title":"Endocrinology"},{"key":"10.1016\/j.xfss.2021.07.002_bib21","doi-asserted-by":"crossref","first-page":"2995","DOI":"10.1210\/jc.2014-1139","article-title":"IGF1R signaling is necessary for FSH-induced activation of AKT and differentiation of human Cumulus granulosa cells","volume":"99","author":"Baumgarten","year":"2014","journal-title":"J Clin Endocrinol Metab"},{"key":"10.1016\/j.xfss.2021.07.002_bib22","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1210\/me.2012-1307","article-title":"IGF-I signaling is essential for FSH stimulation of AKT and steroidogenic genes in granulosa cells","volume":"27","author":"Zhou","year":"2013","journal-title":"Mol Endocrinol"},{"key":"10.1016\/j.xfss.2021.07.002_bib23","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1016\/j.urolonc.2010.11.001","article-title":"Insulin-like growth factor-1 is associated with regulation of the luteinizing hormone production in men receiving androgen deprivation therapy with gonadotropin-releasing hormone analogues for localized prostate cancer","volume":"30","author":"Hara","year":"2012","journal-title":"Urol Oncol"},{"key":"10.1016\/j.xfss.2021.07.002_bib24","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1677\/JOE-09-0232","article-title":"The role of IGF1 on the differentiation of prolactin secreting cells in the mouse anterior pituitary","volume":"203","author":"Hikake","year":"2009","journal-title":"J Endocrinol"},{"key":"10.1016\/j.xfss.2021.07.002_bib25","doi-asserted-by":"crossref","first-page":"8203","DOI":"10.1038\/s41598-017-08491-z","article-title":"Engineered endothelium provides angiogenic and paracrine stimulus to grafted human ovarian tissue","volume":"7","author":"Man","year":"2017","journal-title":"Sci Rep"},{"key":"10.1016\/j.xfss.2021.07.002_bib26","first-page":"57472","article-title":"Co-transplantation of human ovarian tissue with engineered endothelial cells: a cell-based strategy combining accelerated perfusion with direct paracrine delivery","author":"Man","year":"2018","journal-title":"J Vis Exp"},{"key":"10.1016\/j.xfss.2021.07.002_bib27","doi-asserted-by":"crossref","first-page":"19288","DOI":"10.1073\/pnas.0805980105","article-title":"Generation of a functional and durable vascular niche by the adenoviral E4ORF1 gene","volume":"105","author":"Seandel","year":"2008","journal-title":"Proc Natl Acad Sci U S A"},{"key":"10.1016\/j.xfss.2021.07.002_bib28","doi-asserted-by":"crossref","DOI":"10.1016\/j.celrep.2020.108027","article-title":"Comparison of human antral follicles of xenograft versus ovarian origin reveals disparate molecular signatures","volume":"32","author":"Man","year":"2020","journal-title":"Cell Rep"},{"key":"10.1016\/j.xfss.2021.07.002_bib29","first-page":"499","article-title":"Insulin-like growth factor-I is a marker for the nutritional state","volume":"13","author":"Hawkes","year":"2015","journal-title":"Pediatr Endocrinol Rev"},{"key":"10.1016\/j.xfss.2021.07.002_bib30","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1210\/me.2013-1093","article-title":"Research resource: preovulatory LH surge effects on follicular theca and granulosa transcriptomes","volume":"27","author":"Christenson","year":"2013","journal-title":"Mol Endocrinol"},{"key":"10.1016\/j.xfss.2021.07.002_bib31","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1095\/biolreprod.108.068304","article-title":"Loss of the protein NUPR1 (p8) leads to delayed LHB expression, delayed ovarian maturation, and testicular development of a sertoli-cell-only syndrome-like phenotype in mice","volume":"79","author":"Million Passe","year":"2008","journal-title":"Biol Reprod"},{"key":"10.1016\/j.xfss.2021.07.002_bib32","doi-asserted-by":"crossref","first-page":"28314","DOI":"10.1016\/S0021-9258(18)46930-X","article-title":"The purification, cloning, and expression of a novel luteinizing hormone-induced mitochondrial protein in MA-10 mouse Leydig tumor cells. Characterization of the steroidogenic acute regulatory protein (StAR)","volume":"269","author":"Clark","year":"1994","journal-title":"J Biol Chem"},{"key":"10.1016\/j.xfss.2021.07.002_bib33","doi-asserted-by":"crossref","first-page":"2093","DOI":"10.1210\/en.2015-1701","article-title":"Characterization of ovarian responses to equine chorionic gonadotropin of aromatase-deficient mice with or without 17\u03b2-estradiol supplementation","volume":"157","author":"Toda","year":"2016","journal-title":"Endocrinology"},{"key":"10.1016\/j.xfss.2021.07.002_bib34","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1530\/REP-13-0190","article-title":"Expression and regulation of secreted phosphoprotein 1 in the bovine corpus luteum and effects on T lymphocyte chemotaxis","volume":"146","author":"Poole","year":"2013","journal-title":"Reproduction"},{"key":"10.1016\/j.xfss.2021.07.002_bib35","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1002\/mrd.21273","article-title":"Characterization of S100A11, a suppressive factor of fertilization, in the mouse female reproductive tract","volume":"78","author":"Hanaue","year":"2011","journal-title":"Mol Reprod Dev"},{"key":"10.1016\/j.xfss.2021.07.002_bib36","article-title":"Short communication: molecular cloning and expression pattern of the porcine 5-aminolevulinate synthase 1 (ALAS1) gene and its association with reproductive traits","volume":"15","author":"Liu","year":"2016","journal-title":"Genet Mol Res"},{"key":"10.1016\/j.xfss.2021.07.002_bib37","doi-asserted-by":"crossref","first-page":"4616","DOI":"10.1210\/jc.2014-2716","article-title":"The loss of luteal progesterone production in women is associated with a galectin switch via \u03b12,6-sialylation of glycoconjugates","volume":"99","author":"Nio-Kobayashi","year":"2014","journal-title":"J Clin Endocrinol Metab"},{"key":"10.1016\/j.xfss.2021.07.002_bib38","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1530\/REP-11-0495","article-title":"Galectin-1 and galectin-3 in the corpus luteum of mice are differentially regulated by prolactin and prostaglandin F2\u03b1","volume":"144","author":"Nio-Kobayashi","year":"2012","journal-title":"Reproduction"},{"key":"10.1016\/j.xfss.2021.07.002_bib39","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1210\/me.2010-0318","article-title":"CCAAT\/enhancer-binding proteins (C\/EBP)-\u03b1 and -\u03b2 are essential for ovulation, luteinization, and the expression of key target genes","volume":"25","author":"Fan","year":"2011","journal-title":"Mol Endocrinol"},{"key":"10.1016\/j.xfss.2021.07.002_bib40","doi-asserted-by":"crossref","first-page":"3010","DOI":"10.1096\/fj.09-145789","article-title":"WNT4 is required for normal ovarian follicle development and female fertility","volume":"24","author":"Boyer","year":"2010","journal-title":"FASEB J"},{"key":"10.1016\/j.xfss.2021.07.002_bib41","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1210\/endo.143.3.8684","article-title":"Regulated expression of Wnts and Frizzleds at specific stages of follicular development in the rodent ovary","volume":"143","author":"Hsieh","year":"2002","journal-title":"Endocrinology"},{"key":"10.1016\/j.xfss.2021.07.002_bib42","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1210\/endo.141.1.7257","article-title":"Expression and localization of serum\/glucocorticoid-induced kinase in the rat ovary: relation to follicular growth and differentiation","volume":"141","author":"Alliston","year":"2000","journal-title":"Endocrinology"},{"key":"10.1016\/j.xfss.2021.07.002_bib43","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1530\/REP-08-0308","article-title":"Gene expression profiling of bovine preovulatory follicles: gonadotropin surge and prostanoid-dependent up-regulation of genes potentially linked to the ovulatory process","volume":"137","author":"Li","year":"2009","journal-title":"Reproduction"},{"key":"10.1016\/j.xfss.2021.07.002_bib44","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1186\/1477-7827-1-85","article-title":"Temporal and spatial expression of tissue inhibitors of metalloproteinases 1 and 2 (TIMP-1 and -2) in the bovine corpus luteum","volume":"1","author":"Zhang","year":"2003","journal-title":"Reprod Biol Endocrinol"},{"key":"10.1016\/j.xfss.2021.07.002_bib45","doi-asserted-by":"crossref","first-page":"467","DOI":"10.3389\/fendo.2019.00467","article-title":"Prostaglandins in superovulation induced bovine follicles during the preovulatory period and early corpus luteum","volume":"10","author":"Berisha","year":"2019","journal-title":"Front Endocrinol (Lausanne)"},{"key":"10.1016\/j.xfss.2021.07.002_bib46","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1267\/ahc.11035","article-title":"Immunohistochemical characterization of S100A6 in the murine ovary","volume":"45","author":"Hanaue","year":"2012","journal-title":"Acta Histochem Cytochem"},{"key":"10.1016\/j.xfss.2021.07.002_bib47","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1016\/S0015-0282(16)53277-4","article-title":"Cotreatment with human growth hormone and gonadotropins for induction of ovulation: a controlled clinical trial","volume":"53","author":"Homburg","year":"1990","journal-title":"Fertil Steril"},{"key":"10.1016\/j.xfss.2021.07.002_bib48","doi-asserted-by":"crossref","first-page":"500","DOI":"10.3389\/fendo.2019.00500","article-title":"Use of growth hormone in the IVF treatment of women with poor ovarian reserve","volume":"10","author":"Hart","year":"2019","journal-title":"Front Endocrinol (Lausanne)"},{"key":"10.1016\/j.xfss.2021.07.002_bib49","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.ejogrb.2018.06.035","article-title":"The addition of growth hormone adjuvant therapy to the long down regulation protocol in poor responders undergoing in\u00a0vitro fertilization: randomized control trial","volume":"228","author":"Dakhly","year":"2018","journal-title":"Eur J Obstet Gynecol Reprod Biol"},{"key":"10.1016\/j.xfss.2021.07.002_bib50","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1016\/j.rbmo.2019.02.003","article-title":"Human growth hormone for poor responders: a randomized placebo-controlled trial provides no evidence for improved live birth rate","volume":"38","author":"Norman","year":"2019","journal-title":"Reprod Biomed Online"},{"key":"10.1016\/j.xfss.2021.07.002_bib51","doi-asserted-by":"crossref","first-page":"592","DOI":"10.20945\/2359-3997000000189","article-title":"Personalized approach to growth hormone replacement in adults","volume":"63","author":"van Bunderen","year":"2019","journal-title":"Arch Endocrinol Metab"}],"container-title":["F&S Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S2666335X21000537?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S2666335X21000537?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T21:06:22Z","timestamp":1762981582000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S2666335X21000537"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8]]},"references-count":51,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2021,8]]}},"alternative-id":["S2666335X21000537"],"URL":"https:\/\/doi.org\/10.1016\/j.xfss.2021.07.002","relation":{},"ISSN":["2666-335X"],"issn-type":[{"value":"2666-335X","type":"print"}],"subject":[],"published":{"date-parts":[[2021,8]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Exogenous insulin-like growth factor 1 accelerates growth and maturation of follicles in human cortical xenografts and increases ovarian output in mice","name":"articletitle","label":"Article Title"},{"value":"F&S Science","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.xfss.2021.07.002","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2021 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.","name":"copyright","label":"Copyright"}]}}