{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T05:04:08Z","timestamp":1789448648031,"version":"build-2803163510"},"reference-count":39,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"14","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2008,4,8]]},"abstract":"<jats:p>\n            <jats:bold>\n              <jats:italic>Background\u2014<\/jats:italic>\n            <\/jats:bold>\n            The B vitamin folic acid (FA) is important to mitochondrial protein and nucleic acid synthesis, is an antioxidant, and enhances nitric oxide synthase activity. Here, we tested whether FA reduces myocardial ischemic dysfunction and postreperfusion injury.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>\n              <jats:italic>Methods and Results\u2014<\/jats:italic>\n            <\/jats:bold>\n            Wistar rats were pretreated with either FA (10 mg\/d) or placebo for 1 week and then underwent in vivo transient left coronary artery occlusion for 30 minutes with or without 90 minutes of reperfusion (total n=131; subgroups used for various analyses). FA (4.5\u00d710\n            <jats:sup>\u22126<\/jats:sup>\n            mol\/L IC) pretreatment and global ischemia\/reperfusion (30 minutes\/30 minutes) also were performed in vitro (n=28). After 30 minutes of ischemia, global function declined more in controls than in FA-pretreated rats (\u0394dP\/dtmax, \u2212878\u00b1586 versus \u22121956\u00b1351 mm Hg\/s placebo;\n            <jats:italic>P<\/jats:italic>\n            =0.03), and regional thickening was better preserved (37.3\u00b15.3% versus 5.1\u00b10.6% placebo;\n            <jats:italic>P<\/jats:italic>\n            =0.004). Anterior wall perfusion fell similarly (\u221278.4\u00b19.3% versus \u221271.2\u00b113.8% placebo at 30 minutes), yet myocardial high-energy phosphates ATP and ADP reduced by ischemia in controls were better preserved by FA pretreatment (ATP: control, 2740\u00b158 nmol\/g; ischemia, 947\u00b155 nmol\/g; ischemia plus FA, 1332\u00b1101 nmol\/g;\n            <jats:italic>P<\/jats:italic>\n            =0.02). Basal oxypurines (xanthine, hypoxanthine, and urate) rose with FA pretreatment but increased less during ischemia than in controls. Ischemic superoxide generation declined (3124\u00b1280 cpm\/mg FA versus 5898\u00b1474 cpm\/mg placebo;\n            <jats:italic>P<\/jats:italic>\n            =0.001). After reperfusion, FA-treated hearts had smaller infarcts (3.8\u00b11.2% versus 60.3\u00b14.1% placebo area at risk;\n            <jats:italic>P<\/jats:italic>\n            &lt;0.002) and less contraction band necrosis, terminal deoxynucleotidyl transferase\u2013mediated dUTP nick-end labeling positivity, superoxide, and nitric oxide synthase uncoupling. Infarct size declined similarly with 1 mg\/d FA.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>\n              <jats:italic>Conclusions\u2014<\/jats:italic>\n            <\/jats:bold>\n            FA pretreatment blunts myocardial dysfunction during ischemia and ameliorates postreperfusion injury. This is coupled to preservation of high-energy phosphates, reducing subsequent reactive oxygen species generation, eNOS-uncoupling, and postreperfusion cell death.\n          <\/jats:p>","DOI":"10.1161\/circulationaha.107.725481","type":"journal-article","created":{"date-parts":[[2008,3,25]],"date-time":"2008-03-25T00:44:06Z","timestamp":1206405846000},"page":"1810-1819","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":102,"title":["High-Dose Folic Acid Pretreatment Blunts Cardiac Dysfunction During Ischemia Coupled to Maintenance of High-Energy Phosphates and Reduces Postreperfusion Injury"],"prefix":"10.1161","volume":"117","author":[{"given":"An L.","family":"Moens","sequence":"first","affiliation":[{"name":"From the Johns Hopkins Medical Institutions, Divisions of Cardiology (A.L.M., H.C.C., A.H., M.Z., D.B., K.L.G., N.P., D.A.K.) and Pathology (R.S.E.), Baltimore, Md; University of Antwerp, Departments of Cardiology (A.L.M., M.J.C., D.J.B., P.C., C.J.V.), Cell Biology and Histology (L.V.N., J.-P.T.), and Biomedical Statistics (F.L.W.), Antwerp, Belgium; University of Rome, Department of Chemical Science, Rome, Italy (B.T., G.L.); and New York Medical College, Department of Physiology, Valhalla (P.M.K...."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hunter C.","family":"Champion","sequence":"additional","affiliation":[{"name":"From the Johns Hopkins Medical Institutions, Divisions of Cardiology (A.L.M., H.C.C., A.H., M.Z., D.B., K.L.G., N.P., D.A.K.) and Pathology (R.S.E.), Baltimore, Md; University of Antwerp, Departments of Cardiology (A.L.M., M.J.C., D.J.B., P.C., C.J.V.), Cell Biology and Histology (L.V.N., J.-P.T.), and Biomedical Statistics (F.L.W.), Antwerp, Belgium; University of Rome, Department of Chemical Science, Rome, Italy (B.T., G.L.); and New York Medical College, Department of Physiology, Valhalla (P.M.K...."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc J.","family":"Claeys","sequence":"additional","affiliation":[{"name":"From the Johns Hopkins Medical Institutions, Divisions of Cardiology (A.L.M., H.C.C., A.H., M.Z., D.B., K.L.G., N.P., D.A.K.) and Pathology (R.S.E.), Baltimore, Md; University of Antwerp, Departments of Cardiology (A.L.M., M.J.C., D.J.B., P.C., C.J.V.), Cell Biology and Histology (L.V.N., J.-P.T.), and Biomedical Statistics (F.L.W.), Antwerp, Belgium; University of Rome, Department of Chemical Science, Rome, Italy (B.T., G.L.); and New York Medical College, Department of Physiology, Valhalla (P.M.K...."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Tavazzi","sequence":"additional","affiliation":[{"name":"From the Johns Hopkins Medical Institutions, Divisions of Cardiology (A.L.M., H.C.C., A.H., M.Z., D.B., K.L.G., N.P., D.A.K.) and Pathology (R.S.E.), Baltimore, Md; University of Antwerp, Departments of Cardiology (A.L.M., M.J.C., D.J.B., P.C., C.J.V.), Cell Biology and Histology (L.V.N., J.-P.T.), and Biomedical Statistics (F.L.W.), Antwerp, Belgium; University of Rome, Department of Chemical Science, Rome, Italy (B.T., G.L.); and New York Medical College, Department of Physiology, Valhalla (P.M.K...."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pawel M.","family":"Kaminski","sequence":"additional","affiliation":[{"name":"From the Johns Hopkins Medical Institutions, Divisions of Cardiology (A.L.M., H.C.C., A.H., M.Z., D.B., K.L.G., N.P., D.A.K.) and Pathology (R.S.E.), Baltimore, Md; University of Antwerp, Departments of Cardiology (A.L.M., M.J.C., D.J.B., P.C., C.J.V.), Cell Biology and Histology (L.V.N., J.-P.T.), and Biomedical Statistics (F.L.W.), Antwerp, Belgium; University of Rome, Department of Chemical Science, Rome, Italy (B.T., G.L.); and New York Medical College, Department of Physiology, Valhalla (P.M.K...."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael S.","family":"Wolin","sequence":"additional","affiliation":[{"name":"From the Johns Hopkins Medical Institutions, Divisions of Cardiology (A.L.M., H.C.C., A.H., M.Z., D.B., K.L.G., N.P., D.A.K.) and Pathology (R.S.E.), Baltimore, Md; University of Antwerp, Departments of Cardiology (A.L.M., M.J.C., D.J.B., P.C., C.J.V.), Cell Biology and Histology (L.V.N., J.-P.T.), and Biomedical Statistics (F.L.W.), Antwerp, Belgium; University of Rome, Department of Chemical Science, Rome, Italy (B.T., G.L.); and New York Medical College, Department of Physiology, Valhalla (P.M.K...."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dirk J.","family":"Borgonjon","sequence":"additional","affiliation":[{"name":"From the Johns Hopkins Medical Institutions, Divisions of Cardiology (A.L.M., H.C.C., A.H., M.Z., D.B., K.L.G., N.P., D.A.K.) and Pathology (R.S.E.), Baltimore, Md; University of Antwerp, Departments of Cardiology (A.L.M., M.J.C., D.J.B., P.C., C.J.V.), Cell Biology and Histology (L.V.N., J.-P.T.), and Biomedical Statistics (F.L.W.), Antwerp, Belgium; University of Rome, Department of Chemical Science, Rome, Italy (B.T., G.L.); and New York Medical College, Department of Physiology, Valhalla (P.M.K...."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luc","family":"Van Nassauw","sequence":"additional","affiliation":[{"name":"From the Johns Hopkins Medical Institutions, Divisions of Cardiology (A.L.M., H.C.C., A.H., M.Z., D.B., K.L.G., N.P., D.A.K.) and Pathology (R.S.E.), Baltimore, Md; University of Antwerp, Departments of Cardiology (A.L.M., M.J.C., D.J.B., P.C., C.J.V.), Cell Biology and Histology (L.V.N., J.-P.T.), and Biomedical Statistics (F.L.W.), Antwerp, Belgium; University of Rome, Department of Chemical Science, Rome, Italy (B.T., G.L.); and New York Medical College, Department of Physiology, Valhalla (P.M.K...."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Azeb","family":"Haile","sequence":"additional","affiliation":[{"name":"From the Johns Hopkins Medical Institutions, Divisions of Cardiology (A.L.M., H.C.C., A.H., M.Z., D.B., K.L.G., N.P., D.A.K.) and Pathology (R.S.E.), Baltimore, Md; University of Antwerp, Departments of Cardiology (A.L.M., M.J.C., D.J.B., P.C., C.J.V.), Cell Biology and Histology (L.V.N., J.-P.T.), and Biomedical Statistics (F.L.W.), Antwerp, Belgium; University of Rome, Department of Chemical Science, Rome, Italy (B.T., G.L.); and New York Medical College, Department of Physiology, Valhalla (P.M.K...."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muz","family":"Zviman","sequence":"additional","affiliation":[{"name":"From the Johns Hopkins Medical Institutions, Divisions of Cardiology (A.L.M., H.C.C., A.H., M.Z., D.B., K.L.G., N.P., D.A.K.) and Pathology (R.S.E.), Baltimore, Md; University of Antwerp, Departments of Cardiology (A.L.M., M.J.C., D.J.B., P.C., C.J.V.), Cell Biology and Histology (L.V.N., J.-P.T.), and Biomedical Statistics (F.L.W.), Antwerp, Belgium; University of Rome, Department of Chemical Science, Rome, Italy (B.T., G.L.); and New York Medical College, Department of Physiology, Valhalla (P.M.K...."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Djahida","family":"Bedja","sequence":"additional","affiliation":[{"name":"From the Johns Hopkins Medical Institutions, Divisions of Cardiology (A.L.M., H.C.C., A.H., M.Z., D.B., K.L.G., N.P., D.A.K.) and Pathology (R.S.E.), Baltimore, Md; University of Antwerp, Departments of Cardiology (A.L.M., M.J.C., D.J.B., P.C., C.J.V.), Cell Biology and Histology (L.V.N., J.-P.T.), and Biomedical Statistics (F.L.W.), Antwerp, Belgium; University of Rome, Department of Chemical Science, Rome, Italy (B.T., G.L.); and New York Medical College, Department of Physiology, Valhalla (P.M.K...."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Floris L.","family":"Wuyts","sequence":"additional","affiliation":[{"name":"From the Johns Hopkins Medical Institutions, Divisions of Cardiology (A.L.M., H.C.C., A.H., M.Z., D.B., K.L.G., N.P., D.A.K.) and Pathology (R.S.E.), Baltimore, Md; University of Antwerp, Departments of Cardiology (A.L.M., M.J.C., D.J.B., P.C., C.J.V.), Cell Biology and Histology (L.V.N., J.-P.T.), and Biomedical Statistics (F.L.W.), Antwerp, Belgium; University of Rome, Department of Chemical Science, Rome, Italy (B.T., G.L.); and New York Medical College, Department of Physiology, Valhalla (P.M.K...."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca S.","family":"Elsaesser","sequence":"additional","affiliation":[{"name":"From the Johns Hopkins Medical Institutions, Divisions of Cardiology (A.L.M., H.C.C., A.H., M.Z., D.B., K.L.G., N.P., D.A.K.) and Pathology (R.S.E.), Baltimore, Md; University of Antwerp, Departments of Cardiology (A.L.M., M.J.C., D.J.B., P.C., C.J.V.), Cell Biology and Histology (L.V.N., J.-P.T.), and Biomedical Statistics (F.L.W.), Antwerp, Belgium; University of Rome, Department of Chemical Science, Rome, Italy (B.T., G.L.); and New York Medical College, Department of Physiology, Valhalla (P.M.K...."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Cos","sequence":"additional","affiliation":[{"name":"From the Johns Hopkins Medical Institutions, Divisions of Cardiology (A.L.M., H.C.C., A.H., M.Z., D.B., K.L.G., N.P., D.A.K.) and Pathology (R.S.E.), Baltimore, Md; University of Antwerp, Departments of Cardiology (A.L.M., M.J.C., D.J.B., P.C., C.J.V.), Cell Biology and Histology (L.V.N., J.-P.T.), and Biomedical Statistics (F.L.W.), Antwerp, Belgium; University of Rome, Department of Chemical Science, Rome, Italy (B.T., G.L.); and New York Medical College, Department of Physiology, Valhalla (P.M.K...."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathy L.","family":"Gabrielson","sequence":"additional","affiliation":[{"name":"From the Johns Hopkins Medical Institutions, Divisions of Cardiology (A.L.M., H.C.C., A.H., M.Z., D.B., K.L.G., N.P., D.A.K.) and Pathology (R.S.E.), Baltimore, Md; University of Antwerp, Departments of Cardiology (A.L.M., M.J.C., D.J.B., P.C., C.J.V.), Cell Biology and Histology (L.V.N., J.-P.T.), and Biomedical Statistics (F.L.W.), Antwerp, Belgium; University of Rome, Department of Chemical Science, Rome, Italy (B.T., G.L.); and New York Medical College, Department of Physiology, Valhalla (P.M.K...."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Lazzarino","sequence":"additional","affiliation":[{"name":"From the Johns Hopkins Medical Institutions, Divisions of Cardiology (A.L.M., H.C.C., A.H., M.Z., D.B., K.L.G., N.P., D.A.K.) and Pathology (R.S.E.), Baltimore, Md; University of Antwerp, Departments of Cardiology (A.L.M., M.J.C., D.J.B., P.C., C.J.V.), Cell Biology and Histology (L.V.N., J.-P.T.), and Biomedical Statistics (F.L.W.), Antwerp, Belgium; University of Rome, Department of Chemical Science, Rome, Italy (B.T., G.L.); and New York Medical College, Department of Physiology, Valhalla (P.M.K...."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nazareno","family":"Paolocci","sequence":"additional","affiliation":[{"name":"From the Johns Hopkins Medical Institutions, Divisions of Cardiology (A.L.M., H.C.C., A.H., M.Z., D.B., K.L.G., N.P., D.A.K.) and Pathology (R.S.E.), Baltimore, Md; University of Antwerp, Departments of Cardiology (A.L.M., M.J.C., D.J.B., P.C., C.J.V.), Cell Biology and Histology (L.V.N., J.-P.T.), and Biomedical Statistics (F.L.W.), Antwerp, Belgium; University of Rome, Department of Chemical Science, Rome, Italy (B.T., G.L.); and New York Medical College, Department of Physiology, Valhalla (P.M.K...."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Pierre","family":"Timmermans","sequence":"additional","affiliation":[{"name":"From the Johns Hopkins Medical Institutions, Divisions of Cardiology (A.L.M., H.C.C., A.H., M.Z., D.B., K.L.G., N.P., D.A.K.) and Pathology (R.S.E.), Baltimore, Md; University of Antwerp, Departments of Cardiology (A.L.M., M.J.C., D.J.B., P.C., C.J.V.), Cell Biology and Histology (L.V.N., J.-P.T.), and Biomedical Statistics (F.L.W.), Antwerp, Belgium; University of Rome, Department of Chemical Science, Rome, Italy (B.T., G.L.); and New York Medical College, Department of Physiology, Valhalla (P.M.K...."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christiaan J.","family":"Vrints","sequence":"additional","affiliation":[{"name":"From the Johns Hopkins Medical Institutions, Divisions of Cardiology (A.L.M., H.C.C., A.H., M.Z., D.B., K.L.G., N.P., D.A.K.) and Pathology (R.S.E.), Baltimore, Md; University of Antwerp, Departments of Cardiology (A.L.M., M.J.C., D.J.B., P.C., C.J.V.), Cell Biology and Histology (L.V.N., J.-P.T.), and Biomedical Statistics (F.L.W.), Antwerp, Belgium; University of Rome, Department of Chemical Science, Rome, Italy (B.T., G.L.); and New York Medical College, Department of Physiology, Valhalla (P.M.K...."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Kass","sequence":"additional","affiliation":[{"name":"From the Johns Hopkins Medical Institutions, Divisions of Cardiology (A.L.M., H.C.C., A.H., M.Z., D.B., K.L.G., N.P., D.A.K.) and Pathology (R.S.E.), Baltimore, Md; University of Antwerp, Departments of Cardiology (A.L.M., M.J.C., D.J.B., P.C., C.J.V.), Cell Biology and Histology (L.V.N., J.-P.T.), and Biomedical Statistics (F.L.W.), Antwerp, Belgium; University of Rome, Department of Chemical Science, Rome, Italy (B.T., G.L.); and New York Medical College, Department of Physiology, Valhalla (P.M.K...."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_2_1_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.ph.47.030185.003455"},{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardiores.2005.12.019"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardiores.2006.06.011"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00041.2002"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardiores.2006.02.025"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00590.2005"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2005.09.011"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.1999.276.5.H1567"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00129.2003"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1097\/01.fjc.0000201360.71813.8a"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi00146a019"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.16.9220"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1161\/res.86.11.1129"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1161\/circulationaha.106.679084"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2005.11.047"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbi.2006.05.010"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00294.2007"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI21968"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.2001.280.1.H108"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00629.2004"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1161\/circulationaha.106.612325"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00294.2007"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)77928-9"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0891-5849(99)00100-8"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1097\/01.fjc.0000242050.16790.65"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2006.10.018"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.atv.0000115637.48689.77"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.res.0000187447.03525.72"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1113\/expphysiol.2006.035113"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1161\/circulationaha.105.602532"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00935.2001"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1161\/circ.100.12.1291"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2362.2006.01739.x"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2005.02.038"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1079\/BJN20041259"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2828(88)80177-9"},{"key":"e_1_3_2_37_2","first-page":"865.","volume":"40","year":"1981","unstructured":"Oster K. 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