{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T17:56:19Z","timestamp":1793642179675,"version":"4.5.1"},"reference-count":38,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2012,10,1]],"date-time":"2012-10-01T00:00:00Z","timestamp":1349049600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2012,10,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Rationale<\/jats:title>\n                    <jats:p>Patients with idiopathic pulmonary arterial hypertension (iPAH) often have a low cardiac output. To compensate, neurohormonal systems such as the renin\u2013angiotensin\u2013aldosterone system (RAAS) and the sympathetic nervous system are up-regulated, but this may have long-term negative effects on the progression of iPAH.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>Assess systemic and pulmonary RAAS activity in patients with iPAH and determine the efficacy of chronic RAAS inhibition in experimental PAH.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We collected 79 blood samples from 58 patients with iPAH in the VU University Medical Center Amsterdam (between 2004 and 2010) to determine systemic RAAS activity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Measurements and Main Results<\/jats:title>\n                    <jats:p>We observed increased levels of renin, angiotensin (Ang)I, and AngII, which were associated with disease progression (P &amp;lt; 0.05) and mortality (P &amp;lt; 0.05). To determine pulmonary RAAS activity, lung specimens were obtained from patients with iPAH (during lung transplantation, n = 13) and control subjects (during lobectomy or pneumonectomy for cancer, n = 14). Local RAAS activity in pulmonary arteries of patients with iPAH was increased, demonstrated by elevated angiotensin-converting enzyme activity in pulmonary endothelial cells and increased AngII type 1 (AT1) receptor expression and signaling. In addition, local RAAS up-regulation was associated with increased pulmonary artery smooth muscle cell proliferation via enhanced AT1 receptor signaling in patients with iPAH compared with control subjects. Finally, to determine the therapeutic potential of RAAS activity, we assessed the chronic effects of an AT1 receptor antagonist (losartan) in the monocrotaline PAH rat model (60 mg\/kg). Losartan delayed disease progression, decreased right ventricular afterload and pulmonary vascular remodeling, and restored right ventricular\u2013arterial coupling in rats with PAH.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Systemic and pulmonary RAAS activities are increased in patients with iPAH and are associated with increased pulmonary vascular remodeling. Chronic inhibition of RAAS by losartan is beneficial in experimental PAH.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1164\/rccm.201203-0411oc","type":"journal-article","created":{"date-parts":[[2012,8,3]],"date-time":"2012-08-03T00:50:58Z","timestamp":1343955058000},"page":"780-789","source":"Crossref","is-referenced-by-count":337,"title":["Dysregulated Renin\u2013Angiotensin\u2013Aldosterone System Contributes to Pulmonary Arterial Hypertension"],"prefix":"10.1093","volume":"186","author":[{"given":"Frances S.","family":"de Man","sequence":"first","affiliation":[{"name":"INSERM UMR 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France"},{"name":"School of Medicine, Universit\u00e9 Paris-Sud, Kremlin-Bic\u00eatre, France"},{"name":"Department of Pulmonology and"},{"name":"Department of Physiology, VU University Medical Center\/Institute of Cardiovascular Research, Amsterdam, The Netherlands; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ly","family":"Tu","sequence":"additional","affiliation":[{"name":"INSERM UMR 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France"},{"name":"School of Medicine, Universit\u00e9 Paris-Sud, Kremlin-Bic\u00eatre, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Louis","family":"Handoko","sequence":"additional","affiliation":[{"name":"Department of Pulmonology and"},{"name":"Department of Physiology, VU University Medical Center\/Institute of Cardiovascular Research, Amsterdam, The Netherlands; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Rain","sequence":"additional","affiliation":[{"name":"Department of Pulmonology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerrina","family":"Ruiter","sequence":"additional","affiliation":[{"name":"Department of Pulmonology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charl\u00e8ne","family":"Fran\u00e7ois","sequence":"additional","affiliation":[{"name":"INSERM UMR 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France"},{"name":"School of Medicine, Universit\u00e9 Paris-Sud, Kremlin-Bic\u00eatre, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid","family":"Schalij","sequence":"additional","affiliation":[{"name":"Department of Pulmonology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Dorfm\u00fcller","sequence":"additional","affiliation":[{"name":"INSERM UMR 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France"},{"name":"School of Medicine, Universit\u00e9 Paris-Sud, Kremlin-Bic\u00eatre, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00e9rald","family":"Simonneau","sequence":"additional","affiliation":[{"name":"INSERM UMR 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France"},{"name":"School of Medicine, Universit\u00e9 Paris-Sud, Kremlin-Bic\u00eatre, France"},{"name":"AP-HP, Service de Pneumologie, Centre de R\u00e9f\u00e9rence de l'Hypertension Pulmonaire S\u00e9v\u00e8re, DHU Thorax Innovation, H\u00f4pital de Bic\u00eatre, Le Kremlin-Bic\u00eatre, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elie","family":"Fadel","sequence":"additional","affiliation":[{"name":"INSERM UMR 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France"},{"name":"School of Medicine, Universit\u00e9 Paris-Sud, Kremlin-Bic\u00eatre, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederic","family":"Perros","sequence":"additional","affiliation":[{"name":"INSERM UMR 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France"},{"name":"School of Medicine, Universit\u00e9 Paris-Sud, Kremlin-Bic\u00eatre, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anco","family":"Boonstra","sequence":"additional","affiliation":[{"name":"Department of Pulmonology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piet E.","family":"Postmus","sequence":"additional","affiliation":[{"name":"Department of Pulmonology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jolanda","family":"van der Velden","sequence":"additional","affiliation":[{"name":"Department of Physiology, VU University Medical Center\/Institute of Cardiovascular Research, Amsterdam, The Netherlands; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anton","family":"Vonk-Noordegraaf","sequence":"additional","affiliation":[{"name":"Department of Pulmonology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Humbert","sequence":"additional","affiliation":[{"name":"INSERM UMR 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France"},{"name":"School of Medicine, Universit\u00e9 Paris-Sud, Kremlin-Bic\u00eatre, France"},{"name":"AP-HP, Service de Pneumologie, Centre de R\u00e9f\u00e9rence de l'Hypertension Pulmonaire S\u00e9v\u00e8re, DHU Thorax Innovation, H\u00f4pital de Bic\u00eatre, Le Kremlin-Bic\u00eatre, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saadia","family":"Eddahibi","sequence":"additional","affiliation":[{"name":"INSERM UMR 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France"},{"name":"School of Medicine, Universit\u00e9 Paris-Sud, Kremlin-Bic\u00eatre, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christophe","family":"Guignabert","sequence":"additional","affiliation":[{"name":"INSERM UMR 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France"},{"name":"School of Medicine, Universit\u00e9 Paris-Sud, Kremlin-Bic\u00eatre, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2012,10,15]]},"reference":[{"key":"2026032101025115800_bib1","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1161\/CIRCULATIONAHA.109.911818","article-title":"Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era","volume":"122","author":"Humbert","year":"2010","journal-title":"Circulation"},{"key":"2026032101025115800_bib2","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1183\/09059180.00007109","article-title":"Perspectives on novel therapeutic strategies for right heart failure in pulmonary arterial hypertension: Lessons from the left heart","volume":"19","author":"Handoko","year":"2010","journal-title":"Eur Respir Rev"},{"key":"2026032101025115800_bib3","doi-asserted-by":"crossref","first-page":"2285","DOI":"10.1161\/01.CIR.94.9.2285","article-title":"Medical therapy can improve the biological properties of the chronically failing heart. A new era in the treatment of heart failure","volume":"94","author":"Eichhorn","year":"1996","journal-title":"Circulation"},{"key":"2026032101025115800_bib4","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1164\/rccm.200912-1856OC","article-title":"Prognostic significance of sympathetic nervous system activation in pulmonary arterial hypertension","volume":"181","author":"Ciarka","year":"2010","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032101025115800_bib5","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1161\/CIRCHEARTFAILURE.111.964494","article-title":"Bisoprolol delays progression towards right heart failure in experimental pulmonary hypertension","volume":"5","author":"de Man","year":"2012","journal-title":"Circ Heart Fail"},{"key":"2026032101025115800_bib6","doi-asserted-by":"crossref","first-page":"1581","DOI":"10.1016\/0735-1097(95)00399-1","article-title":"Neurohormonal activation in patients with right ventricular failure from pulmonary hypertension: relation to hemodynamic variables and endothelin levels","volume":"26","author":"Nootens","year":"1995","journal-title":"J Am Coll Cardiol"},{"key":"2026032101025115800_bib7","doi-asserted-by":"crossref","first-page":"1308","DOI":"10.1161\/01.CIR.0000140724.90898.D3","article-title":"Increased sympathetic nerve activity in pulmonary artery hypertension","volume":"110","author":"Velez-Roa","year":"2004","journal-title":"Circulation"},{"key":"2026032101025115800_bib8","doi-asserted-by":"crossref","first-page":"1364","DOI":"10.1164\/rccm.200712-1876OC","article-title":"Hyponatremia predicts right heart failure and poor survival in pulmonary arterial hypertension","volume":"177","author":"Forfia","year":"2008","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032101025115800_bib9","doi-asserted-by":"crossref","first-page":"27","DOI":"10.3317\/jraas.2003.003","article-title":"Angiotensin-converting enzyme DD genotype in patients with primary pulmonary hypertension: Increased frequency and association with preserved haemodynamics","volume":"4","author":"Abraham","year":"2003","journal-title":"J Renin Angiotensin Aldosterone Syst"},{"key":"2026032101025115800_bib10","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/j.healun.2009.01.016","article-title":"Polymorphism in the angiotensin II type 1 receptor (AGTR1) is associated with age at diagnosis in pulmonary arterial hypertension","volume":"28","author":"Chung","year":"2009","journal-title":"J Heart Lung Transplant"},{"key":"2026032101025115800_bib11","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1002\/1096-9896(2000)9999:9999<::AID-PATH715>3.0.CO;2-Q","article-title":"Expression of pulmonary vascular angiotensin-converting enzyme in primary and secondary plexiform pulmonary hypertension","volume":"192","author":"Orte","year":"2000","journal-title":"J Pathol"},{"key":"2026032101025115800_bib12","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1146\/annurev.pharmtox.010909.105610","article-title":"Tissue renin-angiotensin-aldosterone systems: targets for pharmacological therapy","volume":"50","author":"Bader","year":"2010","journal-title":"Annu Rev Pharmacol Toxicol"},{"key":"2026032101025115800_bib13","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1161\/01.CIR.67.1.155","article-title":"Captopril in primary pulmonary hypertension","volume":"67","author":"Leier","year":"1983","journal-title":"Circulation"},{"key":"2026032101025115800_bib14","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.1164\/rccm.200811-1678OC","article-title":"Evidence for angiotensin-converting enzyme 2 as a therapeutic target for the prevention of pulmonary hypertension","volume":"179","author":"Ferreira","year":"2009","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032101025115800_bib15","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1164\/rccm.200912-1840OC","article-title":"The angiotensin-converting enzyme 2\/angiogenesis-(1\u20137)\/Mas axis confers cardiopulmonary protection against lung fibrosis and pulmonary hypertension","volume":"182","author":"Shenoy","year":"2011","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032101025115800_bib16","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1016\/j.bcp.2007.08.012","article-title":"Angiotensin-converting enzyme 2 and new insights into the renin-angiotensin system","volume":"75","author":"Lambert","year":"2008","journal-title":"Biochem Pharmacol"},{"key":"2026032101025115800_bib17","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1161\/01.CIR.103.6.904","article-title":"Angiotensin II type 1 receptor blockers","volume":"103","author":"Burnier","year":"2001","journal-title":"Circulation"},{"key":"2026032101025115800_bib18","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.1016\/S0140-6736(95)92411-6","article-title":"Angiotensin receptor antagonists: focus on losartan","volume":"346","author":"Johnston","year":"1995","journal-title":"Lancet"},{"key":"2026032101025115800_bib19","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1254\/jphs.09112FP","article-title":"Effects of telmisartan on right ventricular remodeling induced by monocrotaline in rats","volume":"111","author":"Okada","year":"2009","journal-title":"J Pharmacol Sci"},{"key":"2026032101025115800_bib20","doi-asserted-by":"crossref","first-page":"H2319","DOI":"10.1152\/ajpheart.00518.2005","article-title":"Prevention of pulmonary vascular remodeling and of decreased BMPR-2 expression by losartan therapy in shunt-induced pulmonary hypertension","volume":"289","author":"Rondelet","year":"2005","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"2026032101025115800_bib21","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1161\/hc3401.093149","article-title":"Cardioprotective effects of ramipril and losartan in right ventricular pressure overload in the rabbit: Importance of kinins and influence on angiotensin II type 1 receptor signaling pathway","volume":"104","author":"Rouleau","year":"2001","journal-title":"Circulation"},{"key":"2026032101025115800_bib22","first-page":"P1516","article-title":"Increased renin-angiotensin-aldosterone system activity in lungs of patients with idiopathic pulmonary arterial hypertension [abstract]","volume":"274S","author":"de Man","year":"2011","journal-title":"Eur Respir J"},{"key":"2026032101025115800_bib23","first-page":"A2494","article-title":"The therapeutic potential of the renin-angiotensin-aldosteron system in idiopathic pulmonary arterial hypertension [abstract]","volume":"185","author":"de Man","year":"2012","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032101025115800_bib24","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1172\/JCI35070","article-title":"Endothelial-derived FGF2 contributes to the progression of pulmonary hypertension in humans and rodents","volume":"119","author":"Izikki","year":"2009","journal-title":"J Clin Invest"},{"key":"2026032101025115800_bib25","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1165\/rcmb.2010-0317OC","article-title":"Autocrine fibroblast growth factor-2 signaling contributes to altered endothelial phenotype in pulmonary hypertension","volume":"45","author":"Tu","year":"2011","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2026032101025115800_bib26","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1161\/CIRCULATIONAHA.108.829713","article-title":"Opposite effects of training in rats with stable and progressive pulmonary hypertension","volume":"120","author":"Handoko","year":"2009","journal-title":"Circulation"},{"key":"2026032101025115800_bib27","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1183\/09031936.00027909","article-title":"Effects of exercise training in patients with idiopathic pulmonary arterial hypertension","volume":"34","author":"de Man","year":"2009","journal-title":"Eur Respir J"},{"key":"2026032101025115800_bib28","doi-asserted-by":"crossref","first-page":"1411","DOI":"10.1164\/rccm.201003-0354OC","article-title":"Diaphragm muscle fiber weakness in pulmonary hypertension","volume":"183","author":"de Man","year":"2011","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032101025115800_bib29","doi-asserted-by":"crossref","first-page":"2532","DOI":"10.1161\/ATVBAHA.107.144154","article-title":"Emerging concepts of regulation of angiotensin II receptors: new players and targets for traditional receptors","volume":"27","author":"Mogi","year":"2007","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"2026032101025115800_bib30","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1152\/physrev.00036.2005","article-title":"Physiology of local renin-angiotensin systems","volume":"86","author":"Paul","year":"2006","journal-title":"Physiol Rev"},{"key":"2026032101025115800_bib31","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1152\/physrev.00011.2009","article-title":"Physiology of kidney renin","volume":"90","author":"Castrop","year":"2010","journal-title":"Physiol Rev"},{"key":"2026032101025115800_bib32","first-page":"IV80","article-title":"Role of neurohormonal mechanisms in determining survival in patients with severe chronic heart failure","volume":"75","author":"Packer","year":"1987","journal-title":"Circulation"},{"key":"2026032101025115800_bib33","doi-asserted-by":"crossref","first-page":"C82","DOI":"10.1152\/ajpcell.00287.2006","article-title":"Angiotensin ii cell signaling: physiological and pathological effects in the cardiovascular system","volume":"292","author":"Mehta","year":"2007","journal-title":"Am J Physiol Cell Physiol"},{"key":"2026032101025115800_bib34","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1161\/01.HYP.29.1.366","article-title":"Angiotensin II signaling in vascular smooth muscle. New concepts","volume":"29","author":"Griendling","year":"1997","journal-title":"Hypertension"},{"key":"2026032101025115800_bib35","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1016\/j.peptides.2010.03.014","article-title":"SRC tyrosine kinase regulates angiotensin II\u2013induced protein kinase Czeta activation and proliferation in vascular smooth muscle cells","volume":"31","author":"Li","year":"2010","journal-title":"Peptides"},{"key":"2026032101025115800_bib36","doi-asserted-by":"crossref","first-page":"1407","DOI":"10.1378\/chest.102.5.1407","article-title":"Short- and long-term hemodynamic effects of captopril in patients with pulmonary hypertension and selected connective tissue disease","volume":"102","author":"Alpert","year":"1992","journal-title":"Chest"},{"key":"2026032101025115800_bib37","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1136\/hrt.48.6.541","article-title":"Haemodynamic and hormonal effects of captopril in primary pulmonary hypertension","volume":"48","author":"Ikram","year":"1982","journal-title":"Br Heart J"},{"key":"2026032101025115800_bib38","doi-asserted-by":"crossref","first-page":"2511","DOI":"10.1016\/j.jacc.2011.06.068","article-title":"Progressive right ventricular dysfunction in patients with pulmonary arterial hypertension responding to therapy","volume":"58","author":"van de Veerdonk","year":"2011","journal-title":"J Am Coll Cardiol"}],"container-title":["American Journal of Respiratory and Critical Care Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ajrccm\/article-pdf\/186\/8\/780\/67247874\/ajrccm_186_8_780.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ajrccm\/article-pdf\/186\/8\/780\/67247874\/ajrccm_186_8_780.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T05:03:02Z","timestamp":1774069382000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ajrccm\/article\/186\/8\/780\/8507777"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,10]]},"references-count":38,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2012,10,15]]},"published-print":{"date-parts":[[2012,10,15]]}},"URL":"https:\/\/doi.org\/10.1164\/rccm.201203-0411oc","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.717953826.793459446","asserted-by":"object"}]},"ISSN":["1073-449X","1535-4970"],"issn-type":[{"value":"1073-449X","type":"print"},{"value":"1535-4970","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2012,10]]},"published":{"date-parts":[[2012,10]]}}}