Can tissue nitric oxide synthesis 2 (iNOS) levels play a role in the pathophysiology of reflux esophagitis?

Objective: Nitric oxide (NO) is a strong dilatator, playing an important role in inflammatory events. Its production is regulated by NO synthase 2 (NOS2/iNOS). Our aim was to compare iNOS in esophageal tissues of patients with erosive or non-erosive reflux esophagitis to that of normal cases. Materials and Methods: The study was conducted in 2019–2020 on patients undergoing upper gastrointestinal (UGI) endoscopy. Study included 30 patients who had no reflux symptoms and were not diagnosed with reflux esophagitis in the UGI endoscopy (control), 22 who had pronounced reflux symptoms but could not be diagnosed with reflux esophagitis in the endoscopy (non-erosive reflux), and 51 who had reflux esophagitis in the endoscopy (erosive reflux esophagitis). Using the enzyme-linked immunosorbent assay, tissue iNOS levels were assessed on samples from the lower end of the esophagus. Results: Average iNOS level was 5.02±1.51 picogram/milliliter (pg/mL) in the normal group and 5.04±1.68 pg/mL in all reflux esophagitis cases. iNOS levels were higher in non-erosive reflux and lower in erosive reflux than in controls. In erosive reflux A, B, and C, iNOS levels were 5.03±1.64, 5.10±2.23, and 4.06±0.02 pg/mL, respectively. The level in erosive reflux C is considerably lower than in the normal group. However, none of the differences between the groups was significant. Conclusions: NO synthase was higher in patients with non-erosive reflux esophagitis and considerably lower in those with erosive reflux C, compared to the normal cases. Although not significant, the differences suggest that NO and iNOS levels may be important in reflux physiopathology.

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Nebivolol Ameliorates Nitric Oxide–Deficient Hypertension

The Scientific World JOURNAL ◽

10.1100/tsw.2002.814 ◽

2002 ◽

Vol 2 ◽

pp. 1676-1684 ◽

Cited By ~ 11

Author(s):

L.A. Fortepiani ◽

M.C. Ortiz ◽

N.M. Atucha ◽

Joaquin Garcia-Estan

Keyword(s):

Nitric Oxide ◽

Arterial Hypertension ◽

Renin Angiotensin System ◽

Plasma Renin ◽

No Synthase ◽

Nitric Oxide Synthesis ◽

Synthesis Inhibitor ◽

Angiotensin System ◽

Calcium Dependent ◽

Adrenoceptor Antagonist

Nebivolol is a new selective beta 1-adrenoceptor antagonist with nitric oxide (NO)–releasing properties. In the present study we have analyzed whether nebivolol affects the development of the arterial hypertension that follows the chronic inhibition of nitric oxide synthesis. Nebivolol (1 mg/kg/day, 14 days) was given concurrently with the NO synthesis inhibitor Nw-nitro-L-arginine methyl ester (L-NAME, 0.1, 1, and 10 mg/kg/day, 14 days) to several groups of rats. Blood pressure, renal function, plasma renin activity (PRA), and NO activity and metabolites were measured at the end of the treatment period. L-NAME treatment alone increased mean arterial pressure dose dependently (103.5 ± 2.4, 110.9 ± 2.0, and 125.8 ± 2.2 mmHg, respectively). Nebivolol completely prevented the development of arterial hypertension in the groups treated with L-NAME at the doses of 0.1 and 1 mg/kg/day and reduced the increase achieved with the L-NAME dose of 10 mg/kg/day (110.3 ± 2.7). There were no differences in glomerular filtration rate or natriuresis between nebivolol-treated and -untreated rats. Plasma nitrates+nitrites and calcium-dependent NO synthase activity in the kidney also decreased dose dependently with L-NAME treatment and nebivolol did not significantly modify it. However, PRA was lower in all groups treated with nebivolol and L-NAME as compared to the rats receiving only L-NAME. These data indicate that nebivolol prevents the development of the arterial hypertension associated with chronic NO deficit and this effect seems to be dependent on the inhibition of renin-angiotensin system.

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Nitric Oxide Synthesis and Regional Cerebral Blood Flow Responses to Hypercapnia and Hypoxia in the Rat

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.1993.10 ◽

1993 ◽

Vol 13 (1) ◽

pp. 80-87 ◽

Cited By ~ 121

Author(s):

D. A. Pelligrino ◽

H. M. Koenig ◽

R. F. Albrecht

Keyword(s):

Nitric Oxide ◽

No Synthase ◽

Nitric Oxide Synthesis ◽

Cerebral Vasculature ◽

Regional Cerebral Blood ◽

Generating Capacity ◽

Baseline Values ◽

The Brain ◽

Hyperemic Response

The role of nitric oxide (NO) synthesis in the cerebral hyperemic responses to hypercapnia and hypoxia was investigated in anesthetized rats. Regional CBF (rCBF) measurements were obtained in the cortex (CX), subcortex (SC), brainstem (BS), and cerebellum (CE) using radiolabeled microspheres. The rCBF responses to either hypercapnia (Paco2 = 70–80 mm Hg) or hypoxia (Paco2 = 40–45 mm Hg) were compared in rat groups studied in the presence and absence of NO synthase inhibition induced via the intravenous infusion of nitro-l-arginine methyl ester (l-NAME, 3 mg kg−1 min−1). Administration of l-NAME under normocapnic/normoxic conditions produced a 40–60% reduction in baseline rCBF values, indicating the presence of a NO “tone” in the cerebral vasculature. Infusion of l-NAME resulted in a substantial attenuation, in all regions measured, of the rCBF increases that normally accompany hypercapnia. In comparing saline-infused to l-NAME-infused rats, the percentage increases in rCBF (from normocapnic baseline values) were 351% versus 166% (CX), 446% versus 199% (SC), 443% versus 206% (BS), and 483% versus 174% (CE), respectively. The rCBF changes from baseline (ΔrCBF in ml 100 g−1 min−1) were 488 versus 57 (CX), 570 versus 60 (SC), 434 versus 72 (BS), and 393 versus 45 (CE), respectively. These differences were all statistically significant ( p < 0.05). During hypoxia, when compared to rats not given l-NAME, inhibition of NO synthase activity resulted in significantly greater ( p < 0.05) percentage increases in rCBF (from normoxic baseline values) in most regions. The changes in non-l-NAME- vs. l-NAME-infused rats were 156% versus 262% (CX), 181% versus 309% (SC), and 210% versus 462% (BS), respectively. When the ΔrCBF values (from normoxic baseline levels) were compared, the changes were greater in the l-NAME group, but the differences were statistically insignificant. The results of this study indicated that NO synthesis is critically involved in the cerebral hyperemic response to hypercapnia but not hypoxia. In fact, the data obtained in the hypoxic groups suggested that reductions in O2 supply may inhibit the NO-generating capacity in the brain.

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Lipopolysaccharides of Brucella abortusand Brucella melitensis Induce Nitric Oxide Synthesis in Rat Peritoneal Macrophages

Infection and Immunity ◽

10.1128/iai.68.3.1740-1745.2000 ◽

2000 ◽

Vol 68 (3) ◽

pp. 1740-1745 ◽

Cited By ~ 28

Author(s):

Luis López-Urrutia ◽

Andrés Alonso ◽

Maria Luisa Nieto ◽

Yolanda Bayón ◽

Antonio Orduña ◽

...

Keyword(s):

Nitric Oxide ◽

Brucella Abortus ◽

Lipid A ◽

Brucella Melitensis ◽

Low Frequency ◽

Peritoneal Macrophages ◽

No Synthase ◽

Human Brucellosis ◽

Inos Mrna ◽

Nitric Oxide Synthesis

ABSTRACT Smooth lipopolysaccharide (S-LPS) and lipid A of Brucella abortus and Brucella melitensis induced the production of nitric oxide (NO) by rat adherent peritoneal cells, but they induced lower levels of production of NO than Escherichia coli LPS. The participation of the inducible isoform of NO synthase (iNOS) was confirmed by the finding of an increased expression of both iNOS mRNA and iNOS protein. These observations might help to explain (i) the acute outcome of Brucella infection in rodents, (ii) the low frequency of septic shock in human brucellosis, and (iii) the prolonged intracellular survival of Brucellain humans.

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ASUPAN LEMAK DAN KADAR NITRIC OXIDE PADA PENDERITA HIPERTENSI PRIMER DAN NORMOTENSI

Jurnal Ilmiah Inovasi ◽

10.25047/jii.v14i3.30 ◽

2016 ◽

Vol 14 (3) ◽

Author(s):

Arinda Lironika Suryana

Keyword(s):

Nitric Oxide ◽

Immunosorbent Assay ◽

T Test ◽

Enzyme Linked Immunosorbent Assay ◽

Cross Sectional ◽

Food Recall

Pola konsumsi tinggi lemak dapat berisiko tinggi terhadap kejadian hipertensi. Konsumsi lemak jenuh berlebihan dapat menimbulkan gangguan fungsi sel endotel pembuluh darah. Adanya kerusakan sel endotel ini kemudian menyebabkan penurunan kemampuan vasodilatasi dinding pembuluh darah sehingga terjadi peningkatan tekanan darah. Hal ini ditandai dengan penurunan kadar nitric oxide pada hipertensi. Penelitian ini bertujuan untuk menganalisis perbedaan asupan lemak dan kadar serum nitric oxide pada penderita hipertensi primer dan normotensi. Penelitian ini merupakan penelitian observasional analitik dengan rancangan cross sectional. Sampel penelitian terdiri dari 15 orang kelompok hipertensi primer dan 15 orang kelompok normal sebagai kelompok pembanding, berusia antara 40-70 tahun, dan yang mengunjungi Rumah Sakit Umum Haji Surabaya. Sampel dibagi secara acak. Pengumpulan data dilakukan melalui wawancara, food recall 2x24 jam dan pemeriksaan sampel darah. Kadar serum Nitric Oxide diukur dengan menggunakan metode ELISA (Enzyme-Linked Immunosorbent Assay). Data dianalisis dengan uji t-test independen. Hasil penelitian menunjukkan bahwa rata-rata tingkat konsumsi lemak lebih tinggi pada penderita hipertensi sedangkan kadar nitric oxide lebih rendah pada penderita hipertensi dibandingkan dengan subyek normal. Secara statistik terdapat perbedaan yang signifikan antara kedua kelompok mengenai kadar serum nitric oxide (p = 0,023) dan tingkat konsumsi lemak (p = 0,004). Kesimpulannya adalah ada perbedaan tingkat konsumsi lemak dan kadar serum nitric oxide antara penderita hipertensi primer dengan normotensi.

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Сhanges in subcellular distribution of lysosomal cysteine proteinases activity in parenchymatous organs of rats under the action of nitric oxide synthesis modulators

Research n Practical Medicine Journal ◽

10.17709/2409-2231-2018-5-3-3 ◽

2018 ◽

Vol 5 (3) ◽

pp. 28-39

Author(s):

M. A. Fomina ◽

A. A. Terent'ev

Keyword(s):

Nitric Oxide ◽

Subcellular Distribution ◽

Cathepsin L ◽

Kidney Tissue ◽

Selective Inhibitor ◽

No Synthase ◽

Nitric Oxide Synthesis ◽

Lysosomal Activity ◽

Lysosomal Fraction ◽

Cathepsin H

Aim. To study the eﬀect of non-selective inhibitor of NO-synthase N-nitro-L-arginine methyl ester (L-NAME) and substrate of nitric oxide synthesis L-arginine on the activity of cathepsins B, L, H and its subcellular distribution in liver, kidney and lung tissues.Materials and methods. The object of study – male rats Wistar line, the material was the cytoplasmic and lysosomal fraction of homogenates of liver, kidney, lung tissues. A non-selective inhibitor of inducible NO-synthase N-nitro-L-arginine methyl ester (L-NAME) was applied at a dose of 25 mg/kg, the substrate of NO synthesis L-arginine – at a dose of 500 mg/kg. Activity of cathepsins B, L, H was defined separately in the cytoplasmic and lysosomal fractions by spectrofluorometry quantitative determination of the specific substrate cleavage product 7-amido-4-methylcoumarin.Results. Suppression of nitric oxide synthesis by non-selective inhibitor of NO-synthase L-NAME (25 mg/kg, 7 days) in the kidney tissue leads to a decrease in the activity of cathepsins В, L, H in lysosomal fraction with a parallel increase in non-lysosomal activity of cathepsin L, in the liver tissue leads to an increase in lysosomal activity of cathepsin H and a decrease in non-lysosomal activity of cathepsin L. The substrate of nitric oxide synthesis L-arginine (500 mg/kg, 10 days) only causes increased activity of cathepsin L in non-lysosomal fraction of liver tissue, leads to increased lysosomal activity of cathepsin H in kidney tissue, the lung tissue shows a significant increase in the activity of the all studied cathepsins in non-lysosomal fraction, accompanied by an increase in lysosomal activity of cathepsins B and H. The revealed changes are associated with the signs of changes in the ratio of pro-enzyme and active forms of cathepsins.Conclusion. The eﬀects of non-selective inhibitor and substrate of nitric oxide synthesis on the total activity of cathepsins B, L and H in parenchymatous organs and its subcellular distribution are tissue-specific and multidirectional in some cases and are accompanied by signs of changes in the ratio of pro-enzyme and enzymatically active forms mainly due to an increase of pro-enzyme forms.

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The biochemical estimation of the nitric oxide system in prenatally stressed rats

Regional blood circulation and microcirculation ◽

10.24884/1682-6655-2021-20-3-61-69 ◽

2021 ◽

Vol 20 (3) ◽

pp. 61-69

Author(s):

L. E. Belyaeva ◽

H. N. Pauliukevich

Keyword(s):

Nitric Oxide ◽

Blood Serum ◽

Oxide System ◽

No Synthase ◽

Female Rats ◽

Male Rats ◽

Nitric Oxide Synthesis ◽

Chronic Unpredictable Stress ◽

Prenatally Stressed ◽

Nitric Oxide System

Introduction. Pregnancy development following unfavorable conditions could facilitate disorders of nitric oxide (NO) production during offspring’s postnatal life and «program» offspring’s cardiovascular diseases. Investigation of particular features and mechanisms of nitric oxide synthesis and action disorders following prenatal stress will promote expansion of considerations about pathogenesis of different cardiovascular diseases and propose new approaches to their prevention and management.The aim of the investigation is to assess the nature of nitric oxide synthesis and action in mature rats whose mothers were exposed to chronic «unpredictable» stress during pregnancy. Materials and methods. Pregnant rats were subdivided into the «control» and «stress» groups (in 20 animals). The rats from the «stress» group were exposed to multiple different stressors at various intervals, such as 1-day famine; 20-min. immobilization in the water at room temperature; 1-day contact with cats’ excrements. In the blood serum of 3-mo offspring (n=96, including «control» males – 24, «control» females – 26, «stress» males – 22, «stress» females – 24) concentration of the stable products of NO degradation – nitrates/nitrites (NO3–/NO2–), endothelial (eNOS) and inducible (iNOS) isoforms of the NO-synthase, inhibitor of NO-synthase asymmetric dimethylargininne (ADMA), cyclic guanosine monophosphate (cGMP), lipid peroxidation products – diene conjugates (DC) and malonic dialdehyde (MDA) and C-reactive protein (hsCRP) was detected. Results. The decrease of eNOS and cGMP concentration (by 12.9 and 31.9 %, respectively), increase of iNOS, hsCRP and ADMA concentration (by 49.9, 20.3 и 63.1 %, respectively) without statistically significant fluctuation in the NO3–/NO2– level and accumulation of DC and MDA by 21.1 % and 1.5 times in a prenatally stressed male rats’ blood serum were found (as compared with «control» male rats). In a blood serum of female rats, whose mothers were exposed to chronic «unpredictable» stress during pregnancy, a tendency to eNOS concentration decreasing, and increase of iNOS by 30.6 %, hsCRP by 23.9 % and MDA by 2.3 times without statistically significant changes in cGMP, ADMA, NO3–/NO2–, and DC concentration were detected (as compared with «control» female rats). Conclusion. Identified changes of the nitric oxide system synthesis and action in the prenatally stressed male rats could argue the high risk of their cardiovascular system lesion.

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Glutamine metabolism to glucosamine is necessary for glutamine inhibition of endothelial nitric oxide synthesis

Biochemical Journal ◽

10.1042/bj3530245 ◽

2001 ◽

Vol 353 (2) ◽

pp. 245-252 ◽

Cited By ~ 45

Author(s):

Guoyao WU ◽

Tony E. HAYNES ◽

Hui LI ◽

Wene YAN ◽

Cynthia J. MEININGER

Keyword(s):

Nitric Oxide ◽

Endothelial Cells ◽

No Synthase ◽

Glutamine Metabolism ◽

No Production ◽

Nitric Oxide Synthesis ◽

Inhibiting Effect ◽

Arginine Transport ◽

Metabolic Basis ◽

Endothelial Nitric Oxide

L-Glutamine is a physiological inhibitor of endothelial NO synthesis. The present study was conducted to test the hypothesis that metabolism of glutamine to glucosamine is necessary for glutamine inhibition of endothelial NO generation. Bovine venular endothelial cells were cultured for 24h in the presence of 0, 0.1, 0.5 or 2mM D-glucosamine, or of 0.2 or 2mM L-glutamine with or without 20µM 6-diazo-5-oxo-L-norleucine (DON) or with 100µM azaserine. Both DON and azaserine are inhibitors of L-glutamine:D-fructose-6-phosphate transaminase (isomerizing) (EC 2.6.1.16), the first and rate controlling enzyme in glucosamine synthesis. Glucosamine at 0.1, 0.5 and 2mM decreased NO production by 34, 45 and 56% respectively compared with controls where glucosamine was lacking. DON (20µM) and azaserine (100µM) blocked glucosamine synthesis and prevented the inhibition of NO generation by glutamine. Neither glutamine nor glucosamine had an effect on NO synthase (NOS) activity, arginine transport or cellular tetrahydrobiopterin and Ca2+ levels. However, both glutamine and glucosamine inhibited pentose cycle activity and decreased cellular NADPH concentrations; these effects of glutamine were abolished by DON or azaserine. Restoration of cellular NADPH levels by the addition of 1mM citrate also prevented the inhibiting effect of glutamine or glucosamine on NO synthesis. A further increase in cellular NADPH levels by the addition of 5mM citrate resulted in greater production of NO. Collectively, our results demonstrate that the metabolism of glutamine to glucosamine is necessary for the inhibition of endothelial NO generation by glutamine. Glucosamine reduces the cellular availability of NADPH (an essential cofactor for NOS) by inhibiting pentose cycle activity, and this may be a metabolic basis for the inhibition of endothelial NO synthesis by glucosamine.

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Cardiopulmonary bypass increases endothelial dysfunction after pulmonary ischaemia-reperfusion in an animal model

European Journal of Cardio-Thoracic Surgery ◽

10.1093/ejcts/ezaa412 ◽

2020 ◽

Author(s):

Jean Selim ◽

Mouad Hamzaoui ◽

Inès Boukhalfa ◽

Zoubir Djerada ◽

Laurence Chevalier ◽

...

Keyword(s):

Nitric Oxide ◽

Cardiopulmonary Bypass ◽

Endothelial Dysfunction ◽

Lung Transplantation ◽

Immunosorbent Assay ◽

Plasma Levels ◽

Vascular Reactivity ◽

Enzyme Linked Immunosorbent Assay ◽

Ischaemia Reperfusion ◽

The Impact

Abstract OBJECTIVES Endothelial dysfunction during ischaemia-reperfusion (IR) is a major cause of primary graft dysfunction during lung transplantation. The routine use of cardiopulmonary bypass (CPB) during lung transplantation remains controversial. However, the contribution of CPB to pulmonary endothelial dysfunction remains unclear. The objective was to investigate the impact of CPB on endothelial dysfunction in a lung IR rat model. METHODS Rats were allocated to 4 groups: (i) Sham, (ii) IR, (iii) CPB and (iv) IR-CPB. The primary outcome was the study of pulmonary vascular reactivity by wire myograph. We also assessed glycocalyx degradation by enzyme-linked immunosorbent assay and electron microscopy and both systemic and pulmonary inflammation by enzyme-linked immunosorbent assay and immunohistochemistry. Rats were exposed to 45 min of CPB and IR. We used a CPB model allowing femoro-femoral support with left pulmonary hilum ischaemia for IR. RESULTS Pulmonary endothelium-dependent relaxation to acetylcholine was markedly reduced in the IR-CPB group (10.7 ± 9.1%) compared to the IR group (50.5 ± 5.2%, P < 0.001), the CPB group (54.1 ± 4.7%, P < 0.001) and the sham group (80.8 ± 6.7%, P < 0.001), suggesting that the association of pulmonary IR and CPB increases endothelial dysfunction. In IR-CPB, IR and CPB groups, vasorelaxation was completely abolished when inhibiting nitric oxide synthase, suggesting that this relaxation process was mainly mediated by nitric oxide. We observed higher syndecan-1 plasma levels in the IR-CPB group in comparison with the other groups, reflecting an increased degradation of glycocalyx. We also observed higher systemic inflammation in the IR-CPB group as shown by the increased plasma levels of IL-1β, IL-10. CONCLUSIONS CPB significantly increased the IR-mediated effects on pulmonary endothelial dysfunction. Therefore, the use of CPB during lung transplantation could be deleterious, by increasing endothelial dysfunction.

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Glycosylation of Circulating IgA in Patients with IgA Nephropathy Modulates Proliferation and Apoptosis of Mesangial Cells

Journal of the American Society of Nephrology ◽

10.1681/asn.v1291862 ◽

2001 ◽

Vol 12 (9) ◽

pp. 1862-1871 ◽

Cited By ~ 1

Author(s):

ALESSANDRO AMORE ◽

PAOLA CIRINA ◽

GIOVANNI CONTI ◽

PAOLA BRUSA ◽

LICIA PERUZZI ◽

...

Keyword(s):

Nitric Oxide ◽

Iga Nephropathy ◽

Mesangial Cells ◽

Enzyme Linked Immunosorbent Assay ◽

Nitric Oxide Synthesis ◽

Lectin Affinity Chromatography ◽

Serum Iga ◽

Proliferation And Apoptosis ◽

Biologic Effects

Abstract. Abnormalities in circulating IgA1 have been demonstrated in patients with IgA nephropathy (IgAN). This study addresses the question of the functional significance of this alteration in creating mesangial injury. Biologic effects of selected IgA glycoforms isolated from serum of IgAN patients and controls and in vitro deglycosylated normal IgA were tested on cultured human mesangial cells (MC). IgA glycoforms, ranging from 250 to 500 kD molecular weight, were isolated by lectin affinity chromatography followed by HPLC. IgA and IgG content was measured by enzyme-linked immunosorbent assay. HPLC fractions were incubated with MC to evaluate proliferation and apoptosis rates and nitric oxide synthesis. Moreover, MC were conditioned with in vitro desialylated and degalactosylated normal IgA. Patients with IgAN displayed increased levels of IgA glycoforms exposing sialic acid in α2,6 linkage with N-acetylgalactosamine (Neu5Acα2,6GalNAc) (P < 0.02) and GalNAc (P < 0.05), indicating truncation of O-linked glycans of IgA1. Moreover, IgA glycoforms with increased exposure of mannose were observed (P < 0.03), suggesting a defective N-linked glycosylation. No modification in IgG glycosylation was detected. When incubated with MC, the IgA glycoforms isolated from patients with increased exposure of GalNAc, Neu5Acα2,6GalNAc, or mannose, significantly depressed the proliferation and increased the apoptotic rate and nitric oxide synthesis activity of cultured MC, in comparison with fractions isolated from controls. Similarly, in vitro desialylated and degalactosylated IgAs significantly depressed the proliferation and enhanced the apoptosis rates of MC. In conclusion, a significant modulation of several human MC functions exerted by serum IgA with increased exposure of GalNAc, Neu5Acα2,6GalNAc, and mannose residues isolated from IgAN patients is reported for the first time.

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