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Department of Geriatric Medicine, Graduate School of Medicine, University of Tokyo, Tokyo1 13-8655, Japan
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Obstructive sleep apnea syndrome (OSAS) is one of the most important risk factors of cardiovascular disorders. In the treatment of OSAS, nasal continuous positive airway pressure (nCPAP) has been widely used and found to be effective. In the present study, we hypothesized that the hypoxic stress caused by obstructive sleep apnea would increase circulating intercellular adhesion molecule-1 (ICAM-1), interleukin-8 (IL-8), and monocyte chemoattractant protein-1 (MCP-1) in untreated OSAS patients compared with an age-matched control group. In addition, we hypothesized that nCPAP may decrease OSAS-induced hypoxic stress and mediators. To examine these hypotheses, we measured circulating ICAM-1 and IL-8 before and after nCPAP therapy in OSAS patients. We observed that nCPAP decreased apnea, desaturation, and the circulating ICAM-1 and IL-8 levels in OSAS patients. The circulating levels of ICAM-1, IL-8, and MCP-1 in untreated OSAS patients were significantly greater than those in the controls. These observations suggest that nCPAP therapy could reduce OSAS-induced hypoxia and generation of inflammatory mediators. Treatment of OSAS using nCPAP can be, therefore, a potential approach to decrease risk of the progression of OSAS-associated disorders.
cytokines; cardiovascular disorders; ischemic heart disease; desaturation magnitude; hypoxic stress; intracellular adhesion molecule-1; monocyte chemoattractant protein-1; interleukin-8
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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RECENTLY, IT HAS BEEN SHOWN that obstructive sleep apnea syndrome (OSAS) is related to obesity, insulin resistance, and diabetes mellitus (17, 28, 33). Moreover, OSAS could be one of the most important risk factors of cardiovascular disorders, including hypertension, ischemic heart disease, and cerebrovascular events (12, 15, 23, 25), whereas hypoxic stress elicited by OSAS may be involved in the development of cardiovascular disorders. However, the exact mechanism remains to be elucidated.
One of the potential mechanisms is that OSAS-induced hypoxic stress increases circulating inflammatory mediators, leading to cardiovascular lesions. It has been recently suggested that atherosclerosis is related to inflammatory process induced by activation of proinflammatory mediators, including adhesion molecules (11) and cytokines (10, 31). To induce leukocyte migration to inflamed tissue, it is essential for leukocytes to adhere to microvascular endothelium (32). Potential mediators responsible for leukocyte attachment to endothelium include intercellular adhesion molecule-1 (ICAM-1), interleukin-8 (IL-8), and monocyte chemoattractant protein-1 (MCP-1). It has been reported that ICAM-1, a member of the immunoglobulin superfamily, is required for leukocyte migration into inflamed area (3, 6, 35) and plays an important role in inflammatory disease, including bronchial asthma, lung injury, and ischemic heart disease (18-22). IL-8, a CXC chemokine that induces the migration and proliferation of endothelial cells and smooth muscle cells, is a potent angiogenic factor that may play a substantial role in atherosclerosis (4, 31). Increased expression of IL-8 has been reported in atherosclerotic lesions and circulating macrophages from patients with atherosclerosis (31). MCP-1 is upregulated in human atherosclerotic plaques, suggesting a role for MCP-1 in the development of early atherosclerotic lesions (5, 10).
Hypoxic stress increases the adherence of neutrophils to endothelial
cells, and this increased adherence is mediated by proinflammatory mediators, including ICAM-1 (2) and IL-8 (13,
30). Furthermore, it has been reported that hypoxia induces the
synthesis and expression of both ICAM-1 and IL-8 via the activation of
nuclear transcription factor (NF)-
B (7, 36, 37).
In the treatment of OSAS, the efficacy of nasal continuous positive airway pressure (nCPAP) has been reported (8, 27). nCPAP improves sleepiness and quality of life in patients with OSAS, probably because nCPAP intervention removes sleeping upper airway collapse and decreases apnea episode (27). Although it is expected that nCPAP may ultimately improve the prognosis of various disorders associated with OSAS, its exact mechanism is not yet proven.
In the present study, we hypothesized that nCPAP may decrease OSAS-induced hypoxic stress and the generation of proinflammatory mediators. To examine this hypothesis, we measured circulating ICAM-1 and IL-8 before and after nCPAP therapy in OSAS patients.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subjects.
Among patients diagnosed as OSAS in our department, 20 male subjects
participated in the present study. As age-matched controls, 10 male
subjects were chosen and studied. No subjects had any history of
cardiovascular, pulmonary, metabolic, or neuromuscular diseases. All
subjects were in a stable condition for 1 mo before the study. The
characteristics of the subjects in the OSAS and normal groups are shown
in Table 1. There were no significant differences in age and body mass index (BMI) between the two groups, whereas apnea index (AI) in the OSAS group was markedly greater than
that in the control.
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Polysomnography. The subjects underwent polysomnography for 2 consecutive nights. The polysomnography included an electroencephalogram, an electrooculogram, an electromyogram of the chin, and an electrocardiogram (DG Compact32, Medelec, Surrey, UK). We monitored ventilation and airflow using inductive plethysmography (Respitrace, Ambulatory Monitoring, Ardsley, NY) and thermistors (Fukuda-Sangyo, Chiba, Japan) placed at the nostril and mouth. Arterial oxygen saturation (SaO2) was continuously measured via pulse oxymeter (Datex, Helsinki, Finland). Data acquisition was performed overnight from 9:00 PM to 6:00 AM the next morning.
Assessment of hypoxic episodes.
To assess OSAS-induced hypoxia, we applied desaturation magnitude (DM)
in this study. Desaturation episodes were defined as hypoxia of
SaO2 <90%. We defined DM as
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Measurements of circulating ICAM-1, IL-8, and MCP-1.
We obtained peripheral blood from the subjects at 9:00 AM before and
after the nCPAP treatment. The blood samples were centrifuged at
250 g and 4°C for 10 min. The serum samples were then
stored at 
80°C until measurements. The concentrations of ICAM-1,
IL-8 and MCP-1 in the serum were measured by ELISA method. The data are
defined as circulating ICAM-1 (cICAM-1), circulating IL-8 (cIL-8), and
circulating MCP-1 (cMCP-1), respectively.
Data analysis. Comparisons of data between each experimental group were carried out with Student's t-test. Data are expressed as means ± SE. P values <0.05 were taken as significant.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Assessment of hypoxic episodes. There were significant differences in baseline DM between the OSAS and normal groups (2.01 ± 0.66 and 0.02 ± 0.01, respectively; P < 0.001), suggesting that the OSAS patients were exposed to significantly greater degree of hypoxia compared with the control subjects.
Baseline measurements of cICAM-1 and cIL-8.
Figure 1 summarizes the cICAM-1 and cIL-8
levels in the baseline measurements. The levels of both cICAM-1 and
cIL-8 in the OSAS group were significantly greater than those in the
normal group.
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Effects of nCPAP on physiological parameters and circulating
mediators.
After nCPAP, the improvement in sleepiness was observed in all of the
OSAS patients who successfully received therapeutic nCPAP.
Consequently, nCPAP significantly decreased apnea and desaturation (Fig. 5).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The results of the present study demonstrate that nCPAP decreased apnea, desaturation, and the circulating ICAM-1 and IL-8 levels in the OSAS patients. In the baseline measurements, the levels of both ICAM-1 and IL-8 in the OSAS group were significantly greater than those in the control group. These observations suggest that nCPAP therapy could reduce OSAS-induced hypoxia and generation of inflammatory mediators, leading to the possible prevention of cardiovascular disorders.
Several issues warrant consideration before the results are discussed. First, we measured circulating ICAM-1 and IL-8 to assess the expression of cell-associated adhesion molecule and chemokine. Whereas this approach has been widely used (11, 20), it remains unclear whether the circulating levels of these mediators might precisely reflect the real expression of molecules attached to the endothelium or leukocytes. Second, the number of subjects in this study is relatively low, although the characteristics of the subjects were well matched. Increasing the number of subjects may be required to confirm the interpretation of the present results, and we should acknowledge this point.
It has been recently postulated that inflammatory process has a crucial
role in the pathogenesis of atherosclerosis, leading to the various
cardiovascular disorders (1, 9). To promote migration of
leukocytes from circulation to inflamed areas, it is essential for
leukocytes to adhere to vascular endothelium via adhesion molecules
(32). Especially, ICAM-1 has been reported to play
important roles in leukocyte migration to inflamed area (2, 3,
29). ICAM-1 is an 80- to 110-kDa glycoprotein consisting of five
immunoglobulin-like domains and a ligand for LFA-1
(18, 32). It has been demonstrated that the ICAM-1/LFA-1 pathway evolves to function in cell-cell adhesion (33) and
mediates various inflammatory diseases (16, 19, 21, 22,
35). Recently, it has been reported that the circulating ICAM-1
levels are higher in patients with ischemic heart disease than
those in controls (20). Moreover, the circulating ICAM-1
level may indicate a risk of future myocardial infarction, suggesting
that antiadhesion therapies can be considered as a novel therapeutic means of cardiovascular disease (26). In the previous
study, we have demonstrated that the circulating ICAM-1 level is
significantly increased compared with the control group, suggesting
that OSAS-induced hypoxia may induce the activation of ICAM-1 and the
inflammation of endothelium in patients with OSAS (24).
This observation may give rise to a hypothesis that the therapy for
OSAS might be a potential approach to prevention of cardiovascular
disorders via antiadhesion mechanism.
Recently, it has been demonstrated that IL-8 may play an important role in the development of atherosclerosis (4, 10, 31). Although monocytes contribute to the development of atherosclerotic lesions, IL-8 is a powerful trigger for firm adhesion of monocytes to vascular endothelium (10). It has been shown that hypoxia induces expression and/or generation of IL-8 (13, 30), indicating that OSAS-associated desaturation could lead to upregulatation of IL-8 expression. In addition, one could presume that the effective therapy for OSAS may attenuate hypoxic stress, which may prevent the development of vascular lesions via the reduction of IL-8 production.
To treat patients with OSAS, nCPAP therapy is widely used, because nCPAP reduces excessive daytime sleepiness and improves quality of life (8, 27). Based on the recent studies, beneficial effects of nCPAP on the prognosis of OSAS-associated diseases are anticipated, but there exists little evidence to prove this notion. We therefore performed this study to address the question whether nCPAP could affect physiological phenomena and production of proinflammatory mediators. We observed that long-term nCPAP was effective to improve sleepiness, nocturnal apnea, and desaturation and that the levels of circulating mediators were reduced after nCPAP. One of the possible explanations is that nCPAP decreases hypoxic episodes, resulting in the reduction of hypoxia-induced inflammation and expression of ICAM-1 and IL-8. Considering the proinflammatory effects of ICAM-1 and IL-8, the attenuated production of these mediators elicited by nCPAP may suggest a novel approach to manage OSAS and prevent OSAS-associated inflammatory diseases.
To assess the severity of hypoxia induced by OSAS, we used DM. Possibly, this parameter may reflect OSAS-induced hypoxic stress more directly than AI. The usual way to assess the degree of OSAS includes the number of apnea episodes, but DM could reflect both decreases in SaO2 and time spent below 90%. However, to accurately analyze the hypoxic stress, exploring other indexes of hypoxic stress may be important and helpful.
We observed that there was a significant correlation between
circulating ICAM-1 and IL-8 in the population studied. It has been
demonstrated that nuclear transcription factor (NF)-B regulates the
synthesis and expression of both ICAM-1 and IL-8 (26, 27). In addition, NF-B is upregulated by hypoxia, leading to the
increased expression of both ICAM-1 and IL-8 (7, 37).
These reports may explain the present findings that there were
significant correlations between desaturation and mediators measured.
We further investigated the level of circulating MCP-1 in the normal and OSAS groups. Recently, it has been reported that the level of MCP-1 is increased in patients with coronary heart disease (14). In the present study, we observed that the level of MCP-1 in the OSAS group was increased compared with that of the normal group. Possibly, the increases in the circulating chemokines, including MCP-1, may play an important role in the pathogenesis in OSAS patients complicated with cardiovascular disease.
In summary, the circulating ICAM-1, IL-8, and MCP-1 levels increased in the OSAS patients compared with the normal subjects. After nCPAP therapy, significant decreases in the levels of ICAM-1 and IL-8 were observed in the OSAS group. Taken together, OSAS-induced hypoxia activates ICAM-1 and IL-8, resulting in the important risk factor of cardiovascular disorders. Treatment of OSAS with the use of nCPAP can be, therefore, a potential approach to decrease risk of the progression of OSAS-associated disorders.
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ACKNOWLEDGEMENTS |
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This work was supported in part by Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan and by Grant-in-Aid for Comprehensive Research on Aging and Health from the Ministry of Health, Labour and Welfare of Japan.
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FOOTNOTES |
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Address for reprint requests and other correspondence: T. Nagase, Dept. of Geriatric Medicine, Faculty of Medicine, Univ. of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan (E-mail: takahide-tky{at}umin.ac.jp).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
September 27, 2002;10.1152/japplphysiol.00177.2002
Received 5 March 2002; accepted in final form 20 September 2002.
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M D Cross, N L Mills, M Al-Abri, R Riha, M Vennelle, T W Mackay, D E Newby, and N J Douglas Continuous positive airway pressure improves vascular function in obstructive sleep apnoea/hypopnoea syndrome: a randomised controlled trial Thorax, July 1, 2008; 63(7): 578 - 583. [Abstract] [Full Text] [PDF]
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P. Faure, R. Tamisier, J-P. Baguet, A. Favier, S. Halimi, P. Levy, and J-L. Pepin Impairment of serum albumin antioxidant properties in obstructive sleep apnoea syndrome Eur. Respir. J., May 1, 2008; 31(5): 1046 - 1053. [Abstract] [Full Text] [PDF]
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 F. Lopez-Jimenez, F. H. Sert Kuniyoshi, A. Gami, and V. K. Somers Obstructive Sleep Apnea: Implications for Cardiac and Vascular Disease Chest, March 1, 2008; 133(3): 793 - 804. [Full Text] [PDF]
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 M. H. Sanders, J. M. Montserrat, R. Farre, and R. J. Givelber Positive Pressure Therapy: A Perspective on Evidence-based Outcomes and Methods of Application Proceedings of the ATS, February 15, 2008; 5(2): 161 - 172. [Abstract] [Full Text] [PDF]
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 N. J. Buchner, B. M. Sanner, J. Borgel, and L. C. Rump Continuous Positive Airway Pressure Treatment of Mild to Moderate Obstructive Sleep Apnea Reduces Cardiovascular Risk Am. J. Respir. Crit. Care Med., December 15, 2007; 176(12): 1274 - 1280. [Abstract] [Full Text] [PDF]
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 W. T. McNicholas Cardiovascular outcomes of CPAP therapy in obstructive sleep apnea syndrome Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2007; 293(4): R1666 - R1670. [Abstract] [Full Text] [PDF]
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A. Foresi, C. Leone, D. Olivieri, and G. Cremona Alveolar-Derived Exhaled Nitric Oxide Is Reduced in Obstructive Sleep Apnea Syndrome Chest, September 1, 2007; 132(3): 860 - 867. [Abstract] [Full Text] [PDF]
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S. Ryan, G. M Nolan, E. Hannigan, S. Cunningham, C. Taylor, and W. T McNicholas Cardiovascular risk markers in obstructive sleep apnoea syndrome and correlation with obesity Thorax, June 1, 2007; 62(6): 509 - 514. [Abstract] [Full Text] [PDF]
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K. Minoguchi, T. Yokoe, T. Tazaki, H. Minoguchi, N. Oda, A. Tanaka, M. Yamamoto, S. Ohta, C. P. O'Donnell, and M. Adachi Silent Brain Infarction and Platelet Activation in Obstructive Sleep Apnea Am. J. Respir. Crit. Care Med., March 15, 2007; 175(6): 612 - 617. [Abstract] [Full Text] [PDF]
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 R. Wolk and V. K. Somers Sleep Apnoea & Hypertension: Physiological bases for a causal relation: Sleep and the metabolic syndrome Exp Physiol, January 1, 2007; 92(1): 67 - 78. [Abstract] [Full Text] [PDF]
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S. Ryan, CormacT. Taylor, and WalterT. McNicholas Predictors of elevated tumour necrosis factor {alpha} level in obstructive sleep apnoea syndrome Eur. Respir. Rev., December 1, 2006; 15(101): 221 - 223. [Abstract] [Full Text] [PDF]
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S. Ryan, C. T. Taylor, and W. T. McNicholas Predictors of Elevated Nuclear Factor-{kappa}B-dependent Genes in Obstructive Sleep Apnea Syndrome Am. J. Respir. Crit. Care Med., October 1, 2006; 174(7): 824 - 830. [Abstract] [Full Text] [PDF]
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 K Palombi, E Renard, P Levy, C Chiquet, C. Deschaux, J P Romanet, and J L Pepin Non-arteritic anterior ischaemic optic neuropathy is nearly systematically associated with obstructive sleep apnoea Br. J. Ophthalmol., July 1, 2006; 90(7): 879 - 882. [Abstract] [Full Text] [PDF]
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A. I. Pack Advances in Sleep-disordered Breathing Am. J. Respir. Crit. Care Med., January 1, 2006; 173(1): 7 - 15. [Abstract] [Full Text] [PDF]
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K. Minoguchi, T. Yokoe, T. Tazaki, H. Minoguchi, A. Tanaka, N. Oda, S. Okada, S. Ohta, H. Naito, and M. Adachi Increased Carotid Intima-Media Thickness and Serum Inflammatory Markers in Obstructive Sleep Apnea Am. J. Respir. Crit. Care Med., September 1, 2005; 172(5): 625 - 630. [Abstract] [Full Text] [PDF]
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S. Teramoto, H. Yamamoto, Y. Yamaguchi, R. Namba, and Y. Ouchi Obstructive Sleep Apnea Causes Systemic Inflammation and Metabolic Syndrome Chest, March 1, 2005; 127(3): 1074 - 1075. [Full Text] [PDF]
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M.I. Polkey, R. Farre, and A.T. Dinh-Xuan Respiratory monitoring: revisiting classical physiological principles with new tools Eur. Respir. J., November 1, 2004; 24(5): 718 - 719. [Full Text] [PDF]
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K. Minoguchi, T. Tazaki, T. Yokoe, H. Minoguchi, Y. Watanabe, M. Yamamoto, and M. Adachi Elevated Production of Tumor Necrosis Factor-{alpha} by Monocytes in Patients With Obstructive Sleep Apnea Syndrome Chest, November 1, 2004; 126(5): 1473 - 1479. [Abstract] [Full Text] [PDF]
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C. W. Atwood Jr, D. McCrory, J. G. N. Garcia, S. H. Abman, and G. S. Ahearn Pulmonary Artery Hypertension and Sleep-Disordered Breathing: ACCP Evidence-Based Clinical Practice Guidelines Chest, July 1, 2004; 126(1_suppl): 72S - 77S. [Abstract] [Full Text] [PDF]
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 A. S. M. Shamsuzzaman, B. J. Gersh, and V. K. Somers Obstructive Sleep Apnea: Implications for Cardiac and Vascular Disease JAMA, October 8, 2003; 290(14): 1906 - 1914. [Abstract] [Full Text] [PDF]
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L. Dyugovskaya, P. Lavie, and L. Lavie Phenotypic and Functional Characterization of Blood {gamma}{delta} T Cells in Sleep Apnea Am. J. Respir. Crit. Care Med., July 15, 2003; 168(2): 242 - 249. [Abstract] [Full Text] [PDF]
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