Atherosclerosis 219 (2011) Contents lists available at ScienceDirect. Atherosclerosis

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1 Atherosclerosis 219 (2011) Contents lists available at ScienceDirect Atherosclerosis journal homepage: The relationship between the morning blood pressure surge and low-grade inflammation on silent cerebral infarct and clinical stroke events Motohiro Shimizu a,b, Joji Ishikawa a, Yuichirou Yano a, Satoshi Hoshide a, Kazuyuki Shimada a, Kazuomi Kario a, a Division of Cardiovascular Medicine, Department of Medicine, Jichi Medical University School of Medicine, Tochigi, Japan b Department of Internal Medicine, Iwakuni City Nishiki Central Hospital, Yamaguchi, Japan article info abstract Article history: Received 10 April 2011 Received in revised form 13 June 2011 Accepted 14 June 2011 Available online 23 June 2011 Keywords: Morning blood pressure surge Inflammation Hypertension Silent cerebral infarcts Stroke Objective: Morning blood pressure surge (MBPS) has been shown to be a risk factor for cardiovascular disease and is associated with vascular remodeling. This study investigated whether the cerebrovascular risk of MBPS is modified by low-grade inflammation. Methods: We evaluated ambulatory BP, high sensitivity C-reactive protein (hscrp), and brain MRI at baseline in 514 Japanese hypertensive patients, and followed them for the incidence of stroke for an average of 41 months (range: 1 68 months, 1751 person-years). Results: MBPS was significantly correlated with the hscrp level in patients with the highest quartile of MBPS, but not in the other quartiles. The odds ratio for silent cerebral infarcts (SCIs) was significantly higher only in patients in the highest quartile of MBPS with higher (above median) hscrp [odds ratio 2.74, 95% confidence interval (CI) ] in comparison with those in other quartiles of MBPS and with lower (below median) hscrp. Conversely, being in the highest quartile of MBPS and having a higher hscrp were independently and additively associated with an increased risk for clinical stroke events (both the highest quartile of MBPS and the higher hscrp; hazard ratio [HR] 5.77, 95%CI , only the highest quartile of MBPS; HR 3.03, 95%CI , only the higher hscrp; HR 2.89, 95%CI ), even after adjusting for confounding factors. Conclusion: Exaggerated MBPS and increased low-grade inflammation independently increase the risk of stroke, while the relationship between exaggerated MBPS and the presence of SCIs is slightly affected by low-grade inflammation Elsevier Ireland Ltd. All rights reserved. 1. Introduction Cardiovascular events such as myocardial infarction, sudden cardiac death and stroke occur most frequently in the morning hours [1 4]. This pattern is parallel to the diurnal variation of blood pressure (BP), which shows a pronounced morning surge [5]. The early morning BP surge (MBPS) detected by ambulatory BP monitoring (ABPM) has been reported to be a risk factor for cardiovascular disease [6], and we found that the MBPS is an independent predictor of stroke events in hypertensive patients [7]. Several cross-sectional studies have also indicated that the MBPS is associated with vascular remodeling such as atherosclerosis, arterial stiffening, and small vessel disease [7 11]. Inflammation also plays an important role in the pathogenesis of atherosclerosis [12], and has been reported to be associated with cerebral small vessel disease [13,14] and clinical stroke events [15,16]. Recently, several studies have reported that the inflammatory status is associated with MBPS [8,17] and MBPS-related atherosclerotic lesions [18]. Therefore, we hypothesized that the association of MBPS with cerebral small vessel disease and adverse clinical stroke events would also be partly attributable to low-grade inflammation. To examine this hypothesis, we analyzed such a relationship in hypertensive patients who were enrolled in the Jichi Medical School ABPM study, wave 1 [7]. 2. Methods 2.1. Study patients Corresponding author at: Division of Cardiovascular Medicine, Department of Medicine, Jichi Medical University School of Medicine, Yakushiji, Shimotsuke, Tochigi , Japan. Tel.: ; fax: address: kkario@jichi.ac.jp (K. Kario). A total of 514 patients were evaluated in this study as a part of the Jichi Medical School ABPM study, wave 1. Details of the Jichi Medical School ABPM study, wave 1 have been reported /$ see front matter 2011 Elsevier Ireland Ltd. All rights reserved. doi: /j.atherosclerosis

2 M. Shimizu et al. / Atherosclerosis 219 (2011) previously [7]. Briefly, we conducted 24-h ABPM at baseline and studied the incidence of stroke during the mean follow-up period of 41 months. The subjects were enrolled consecutively from outpatient clinics when they were treated or evaluated for hypertension and agreed to participate in this study. The inclusion criteria were: (1) average clinic SBP >140 mm Hg and/or average clinic diastolic BP (DBP) >90 mm Hg on 2 visits; (2) age >50 years; and (3) a successful 24-h ABPM. The patients with renal failure (serum creatinine level >176 mmol/l), hepatic damage, obvious present illness (e.g., malignancy or infection), a past history of coronary artery disease, stroke (including transient ischemic attacks), congestive heart failure, arrhythmia (including atrial fibrillation), or peripheral vascular disease at baseline were excluded from this study. We initially enrolled 821 patients, and measurement of high sensitivity C-reactive protein (hscrp) at baseline and follow up was successfully conducted in 811 patients. Among these, we excluded 297 patients who did not agree to undergo brain MRI (296 patients) or for whom there was incomplete data (one patient). The patients evaluated in this study (514 patients) did not differ markedly with regard to baseline characteristics from the rest of the patients who participated in the Jichi Medical School ABPM study, wave 1; however, they had a significantly higher value of body mass index (BMI), higher prevalence of hyperlipidemia, and a higher percentage of antihypertensive medication use than the other subjects [13]. Diabetes mellitus was defined as a fasting plasma glucose level 126 mg/dl (7.0 mmol/l), a casual plasma glucose level 200 mg/dl (11.1 mmol/l) with symptoms of hyperglycemia, a 2-h plasma glucose level 200 mg/dl (11.1 mmol/l) during an oral glucose tolerance test [19] or the use of an oral hypoglycemic agent or insulin. Impaired fasting glucose (IFG) was defined as a fasting plasma glucose level in the range of mg/dl ( mmol/l) [19]. Glycemic abnormality was defined as either diabetes or IFG. Hyperlipidemia was defined as a total cholesterol level >6.2 mmol/l (240 mg/dl) or the use of an oral lipid-lowering agent. Smokers were defined as current smokers. BMI was calculated as the weight (kg)/height (m 2 ). All patients gave their informed consent. This study was approved by the Research Ethics Committee, Department of Cardiology, Jichi Medical School, Japan. Some of the data from the JMS-ABPM study were published previously [7,13,20,21] BP measurements and analysis of ABPM data The clinic BP was measured after the patients had rested for at least 5 min in the sitting position. Noninvasive ABPM was performed on a weekday with automatic devices (ABPM-630, Nippon Colin Co. [22], TM-2421 or TM-2425, A&D Co. Inc., Japan [23]) that recorded the BP and pulse rate every 30 min for 24 h. No patient had taken any antihypertensive medication for at least 14 days before the ABPM study. We excluded subjects from whom we obtained valid BP readings in <80% in either awake or sleeping states, and those who reported in our post-abpm questionnaire that wearing the ABPM severely disturbed their sleep. The morning BP was defined as the average of BPs during the first 2 h after awaking (4 BP readings). The lowest BP was defined as the average BP of 3 readings centered on the lowest nighttime reading (i.e., the lowest reading plus the readings immediately before and after). MBPS was calculated as the morning SBP minus the lowest SBP [7]. Sleep BP was defined as the average of BPs from the time when the patient went to bed until the time he or she got out of bed, and the awake BP was defined as the average of BPs recorded during the rest of the day. Non-dippers and dippers were defined as those with sleep/awake SBP rates >0.9 and 0.9, respectively. The systolic pressures were used for all these calculations. These periods were estimated from the diaries of the subjects Blood samples Blood samples were drawn from the cubital vein in the fasting state within 2 months of the day of ABPM. Measurements of the serum hscrp level were conducted from 1992 to 1998 and the samples of serum were frozen at 80 C until measurement. The serum hscrp level was measured by nephelometry (NA Latex CRP kit; Dade Behring) by SRL, Inc. When the hscrp value was below the limit of detection (0.03 mg/l), it was recorded as mg/l. Sixtyeight patients had serum hscrp levels below the limit of detection. We defined the cutoff value for identifying higher or lower hscrp as a median hscrp level of 0.21 mg/l based on our previous study [13] Brain MRI Brain MRI was carried out using a superconducting magnet with a main strength of 1.5 T (MRT200FXII; Toshiba; SIGNA-Horizon Ver.5.8; General Electric Co. or Vision; SIEMENS) within 3 months of the ABPM study. T1- and T2-weighted images were obtained in the transverse plane with mm-thick sections. A SCI was defined as a low signal intensity area (3 15 mm) on T1- weighted images that was also visible as a hyperintense lesion on T2-weighted images as described previously [7]. The MRI images of the subjects were randomly stored and interpreted by 2 neurologists who were blinded to the subjects names and characteristics, and the reproducibility of the MRI reading was demonstrated previously [20] Follow-up and events The patients medical records were reviewed after ABPM for the use of antihypertensive drugs and the occurrence of cardiovascular events. The collection of the follow-up data was performed once at the time of the patients clinics visits from 1996 to 1998 (20- month period); the mean follow-up period was 41 months (range: 1 68 months, 1751 person-years). When patients failed to come to the clinic, we interviewed them by telephone. Stroke events were diagnosed by each physician who was caring for the patient at the time of the event, and independent neurologists reviewed the cases and confirmed the diagnosis of stroke events. The criteria for the diagnosis of stroke were sudden onset of neurologic deficit that persisted for 24 h in the absence of any other disease process that could explain the symptom. Stroke events were categorized as ischemic stroke (cerebral atherothrombosis and cerebral embolism), hemorrhagic stroke (cerebral hemorrhage and subarachnoid hemorrhage) and undefined type of stroke. We excluded transient ischemic attacks in which the neurologic deficit cleared completely within 24 h from the onset of symptoms Statistical analysis Statistical analyses were conducted for 514 patients. All data are expressed as the means ± SD or percentage. The serum hscrp level had a skewed deviation, and the analysis of the hscrp level was performed for the raw hscrp value and the log-transformed value. The association between continuous variables was assessed by the Pearson s correlation coefficient. A stepwise multiple linear regression analysis was performed to determine the independence of the association from age, gender, BMI, smoking status, the presence of a glycemic abnormality, the presence of hyperlipidemia, 24-h SBP, and MBPS with the hscrp level. The Chi-square test was used to compare proportions, and one-way analysis of variance was performed to detect differences among groups, and Tukey s honestly significant differences test was used for multiple pairwise comparisons of means among groups. The odds ratio (OR) and the

3 318 M. Shimizu et al. / Atherosclerosis 219 (2011) Table 1 Baseline characteristics of patients. The lower 3 quartiles of MBPS The highest quartile of MBPS P Value Below median hscrp (n = 193) Above median hscrp (n = 193) Below median hscrp (n = 63) Above median hscrp (n = 65) Age (years) 70.2 ± ± ± ± 7.6 <0.001 Male (%) Body mass index (kg/m 2 ) 24.1 ± ± ± ± Current smoker (%) Diabetes + IFG (%) Hyperlipidemia (%) Clinic SBP (mm Hg) ± ± ± ± Clinic DBP (mm Hg) 91.4 ± ± ± ± Clinic PR (mm Hg) 76.2 ± ± ± ± h SBP (mm Hg) ± ± ± ± h DBP (mm Hg) 78.2 ± ± ± ± h PR (mm Hg) 70.2 ± ± ± ± Non-dipper (%) <0.001 MBPS (mm Hg) 25.2 ± ± ± ± 15.3 <0.001 Silent cerebral infarcts (%) Mean hscrp (mg/l) 0.08 ± ± ± ± 0.65 <0.001 Median hscrp (mg/l) Geometric mean hscrp (mg/l) <0.001 Data are shown as the means ± standard deviation or percentage. The Chi-square test was used to compare proportions, and one-way analysis of variance was performed to detect differences among groups. MBPS, morning blood pressure surge; hscrp, high-sensitivity C-reactive protein; IFG, impaired fasting glucose; SBP, systolic blood pressure; DBP, diastolic blood pressure; PR, pulse rate. 95% confidence interval (CI) for the presence of SCIs were calculated using multiple logistic regression analysis. The hazard ratio (HR) and 95%CI of clinical stroke events were calculated using Cox regression analyses before and after adjustments for significant covariates. The statistical calculations were performed using the computer software package SPSS version 11.0 (SPSS Inc., Chicago, USA). A two-tailed P value <0.05 was considered to be statistically significant. 3. Results 3.1. Baseline characteristics The age of the subjects in the present study ranged from 50 to 94 years (mean ± SD: 72.3 ± 8.7 years) and there were 191 males and 323 females. Among the subjects, there were 74 (14.4%) patients with diabetes, 147 (28.6%) with IFG, and 114 (22.2%) current smokers. A history of hyperlipidemia was noted in 112 patients (21.8%). The median hscrp level was 0.21 mg/l (25 75% interquartile ranges, mg/l) and the mean hscrp level was 0.36 mg/l. Although there was no significant correlation between the MBPS and log-transformed hscrp (r = 0.05, P = 0.291) in the entire study population, there was a significant correlation of the MBPS with the log-transformed hscrp (r = 0.19, P = 0.035) in patients with the highest quartile of MBPS. This positive correlation in patients with the highest quartile of MBPS remained statistically significant (ˇ = 0.19, P = 0.038) even after adjusting for the known risk factors of age, gender, BMI, smoking status, the presence of a glycemic abnormality, the presence of hyperlipidemia, and the 24-h SBP. The baseline characteristics of the patients with either the highest quartile or the lower 3 quartiles of MBPS and with higher or lower hscrp levels are shown in Table 1. The patients with the lower 3 quartiles of MBPS and below the median hscrp level were younger than those in the other groups. The gender, BMI, the prevalence of hyperlipidemia, BP values, and pulse rate values were similar among the four groups. The percentage of non-dippers was lower in the patients with the highest quartile of MBPS than in those with the lower 3 quartiles of MBPS. Table 2 Logistic regression analysis for the presence of silent cerebral infarcts. OR 95%CI P Value Age, by 10 years <0.001 Gender (female = 0, male = 1) Body mass index (kg/m 2 ) Current smoking (no = 0, yes = 1) Diabetes + IFG (no = 0, yes = 1) Dipper vs. non-dipper h SBP, 10 mm Hg MBPS, 10 mm Hg Lower hscrp vs. higher hscrp OR, 95%CI, and P values were calculated by logistic regression analysis. OR, odds ratio; CI, confidence interval; IFG, impaired fasting glucose; SBP, systolic blood pressure; MBPS, morning blood pressure surge; hscrp, high-sensitivity C- reactive protein Risks of MBPS and hscrp for SCIs The patients with SCIs had a significantly higher degree of MBPS (35.0 ± 18.8 mm vs ± 15.9 mm Hg, P = 0.030) and higher hscrp levels (geometric mean hscrp: 0.21 mg/l vs mg/l, P < 0.001) than those without SCIs, as in our previous reports [7,13]. In logistic regression analysis adjusting for known covariates of age, gender, BMI, smoking status, the presence of a glycemic abnormality, dipping status, and 24-h SBP, an increased MBPS [10 mm Hg increase: OR 1.12, 95%CI , P = 0.049] and a higher hscrp [higher hscrp level vs. lower hscrp level: OR 1.52, 95%CI , P = 0.030] were independently associated with the presence of SCIs (Table 2). When we analyzed possible interactions between MBPS and hscrp; there was a significant interaction between MBPS and the log-transformed hscrp with the risk of the presence of SCIs (P = 0.042). The ORs for the presence of SCIs in the patients with either the highest quartile or the lower 3 quartiles of MBPS and with higher or lower hscrp levels after adjusting for known covariates of age, gender, BMI, smoking status, the presence of a glycemic abnormality, dipping status, and 24-h SBP are shown in Fig. 1. The ORs for SCIs were significantly higher only in patients with both the highest quartile of MBPS and the higher hscrp level [OR 2.74, 95%CI , P = 0.003] in comparison

4 M. Shimizu et al. / Atherosclerosis 219 (2011) Below median hscrp * Above median hscrp ( ) Below median hscrp 5.0 Above median hscrp 5.77 ( ) ** Odds ra o ( ) The lower 3 quartiles of MBPS 1.08 ( ) N=193 N=193 N=63 N=65 The highest quartile of MBPS Fig. 1. Odds ratios for silent cerebral infarcts. The ORs are adjusted for known covariates such as age, gender, body mass index, smoking status, the presence of a glycemic abnormality, dipping status, and 24-h SBP by logistic regression analysis. *P < 0.01 vs. the patients with the lower 3 quartiles of MBPS and below the median hscrp level. SBP, systolic blood pressure; hscrp, high-sensitivity C-reactive protein; MBPS, morning blood pressure surge. Table 3 Cox regression analysis for clinical stroke events. HR 95%CI P Age, 10 years Antihypertensive medication (no = 0, yes = 1) Antiplatelet medication (no = 0, yes = 1) h SBP, 10 mm Hg <0.001 Silent cerebral infarct (no = 0, yes = 1) MBPS, 10 mm Hg Lower hscrp vs. higher hscrp HR, 95%CI, and P value were calculated by Cox regression analysis. HR, hazard ratio; CI, confidence interval; SBP, systolic blood pressure; MBPS, morning blood pressure surge; hscrp, high-sensitivity C-reactive protein. to those with the lower 3 quartiles of MBPS and the lower hscrp level Risks of MBPS and hscrp for clinical stroke events During an average follow-up duration of 41 months, 43 stroke events occurred (30 ischemic strokes, 5 cerebral hemorrhages, 8 unknown stroke events). The patients with clinical stroke events had a marginally significantly lesser use of antihypertensive medications (41.9% vs. 58.2%, P = 0.053) and a significantly greater use of antiplatelet medication use (51.2% vs. 34.0%, P = 0.030) than those without stroke events, as in our previous reports [13,24]. In Cox regression analysis adjusting for the significant covariates of age, antihypertensive medication use, antiplatelet medication use, 24-h SBP, and the presence of SCIs, increased MBPS [10 mm Hg increase: HR 1.22, 95%CI , P = 0.008] and a higher hscrp [higher hscrp level vs. lower hscrp level: HR 2.47, 95%CI , P = 0.011] were the independent risk factors for clinical stroke events (Table 3). Even after adjustment for known covariates of age, gender, BMI, smoking status, the presence of a glycemic abnormality, antihypertensive medication use, antiplatelet medication use, dipping status, 24-h SBP, and the presence of SCIs, both MBPS and hscrp were independently associated with clinical stroke events. Moreover, no interactions between MBPS and the log-transformed hscrp on risk of the incidence of stroke were observed (P = 0.704). Since we previously reported that the increased hscrp is affected by the presence of SCIs [13], we evaluated parallel Cox regression analyses in patients with/without SCIs separately. Among the patients without SCIs, neither MBPS nor hscrp were independent risk factors for clinical stroke events; on the contrary, among the patients with SCIs, both increased MBPS and a higher hscrp were independent risk factors for clinical stroke events. azard ra o o H * ( ) The lower 3 quartiles of MBPS 3.03 ( ) N=193 N=193 N=63 N=65 The highest quartile of MBPS Fig. 2. The hazard ratio for clinical stroke events. The ratios are adjusted for known covariates such as age, gender, body mass index, smoking status, the presence of a glycemic abnormality, antihypertensive medication use, antiplatelet medication use, dipping status, the presence of SCIs, and the 24-h SBP by Cox regression analysis. *P < 0.05 and **P < 0.01 vs. the patients with the lower 3 quartiles of MBPS and below the median hscrp level. SCIs, silent cerebral infarcts; SBP, systolic blood pressure; hscrp, high-sensitivity C-reactive protein; MBPS, morning blood pressure surge. In Cox regression analysis for clinical stroke events in the patients with either the highest quartile or the lower 3 quartiles of MBPS, and with a higher or lower hscrp level, the patients with both the higher hscrp level and the highest quartile of MBPS [HR 5.77, 95%CI , P = 0.001] and the patients with the high hscrp level and the lower 3 quartiles of MBPS [HR 2.89, 95%CI , P = 0.028] had a significantly higher risk of clinical stroke events than those who had an hscrp level below the median and the lower 3 quartiles of MBPS after adjustments for the known covariates (Fig. 2). After excluding hemorrhagic stroke and undefined type of stroke as end points, we again analyzed the risk of MBPS and hscrp for clinical ischemic stroke events. In Cox regression analysis adjusting for the significant covariates of age, antihypertensive medication use, antiplatelet medication use, 24-h SBP, and the presence of SCIs, increased MBPS [10 mm Hg increase: HR 1.23, 95%CI , P = 0.018] and a higher hscrp [higher hscrp level vs. lower hscrp level: HR 2.85, 95%CI , P = 0.017] were the independent risk factors for clinical ischemic stroke events. Additionally, no interactions between MBPS and the log-transformed hscrp were observed (P = 0.841). 4. Discussion In the present study, the patients with both exaggerated MBPS and a higher hscrp level had a significantly higher risk for SCIs than the others; however, for clinical stroke events, exaggerated MBPS and higher hscrp independently and additively increased the risk. The relationship between an exaggerated MBPS and the presence of SCIs seemed to be slightly affected by low-grade inflammation in this analysis. Previously, Marfella et al. demonstrated that carotid plaques in hypertensive patients with exaggerated MBPS were associated with the characteristics of vulnerable plaques, including increased levels of markers of oxidative stress, and activation of the ubiquitin proteasome system, suggesting that exaggerated MBPS is associated with vascular inflammation [18]. Either elevated cyclic strain or disturbed shear stress on the vascular wall has also been shown to be correlated with vascular inflammation [25,26]. On the other hand, it has been suggested that the BP change induces small artery remodeling though increased mechanical pressure or disturbed shear stress on the vessel wall, and inflammation facilitates this process [27]. Furthermore, structural changes of resistance arteries were shown to be positively associated with MBPS [11]. Therefore, it is possible that the exaggerated MBPS might be related to the vascular remodeling through

5 320 M. Shimizu et al. / Atherosclerosis 219 (2011) both increased BP changed and vascular inflammation. Additionally, it has also been considered that structural alterations in the resistance vasculature could amplify the effects of hypertensive stimuli and thus cause an exaggerated MBPS. We previously reported that elevation of hscrp was attributable to the presence of SCIs (hypertensive target organ damage in the brain) and that it increased the risk of stroke in addition to the presence of SCIs [13]. Taken together, there were two possibilities regarding the relationship among SCIs, exaggerated MBPS, and low-grade inflammation: First, an exaggerated MBPS would cause cerebral small vessel disease in relation to low-grade inflammation, and second, both an exaggerated MBPS and elevated hscrp might be the consequence of hypertensive target organ damage; however no cause effect relationships can be inferred from the present study. Therefore, prospective studies are required to elucidate whether exaggerated MBPS precedes or is the consequence of either the inflammatory status or vascular remodeling. In contrast to this finding, we noted that an exaggerated MBPS and higher hscrp independently and additively increased the risk of clinical stroke events in the present study. Moreover, no interactions between MBPS and hscrp on the risk of the incidence of stroke were observed. This indicates that an exaggerated MBPS and increased low-grade inflammation have different pathophysiological mechanisms with regard to the incidence of stroke. It therefore appears that the exaggerated MBPS is important as a triggering risk factor for stroke events, particularly in high-risk hypertensive patients with the presence of SCIs, independent of their inflammatory status. In this study, the positive relationship between the MBPS and hscrp was demonstrated only in patients with an exaggerated MBPS, and we could not found a significant relationship between these factors in the whole study population. This may indicate that the relationship between the MBPS and hscrp was not linear. Moreover, the hscrp was not significantly different between patients with/without exaggerated MBPS. However Marfella et al. reported that the patients with an exaggerated MBPS had a higher hscrp level than the other patients [8]. We believe that the different BMI levels in Marfella s study and the present study may be responsible for these discrepancies. The mean BMI was 24.2 kg/m 2 in the present study, while it was approximately 27 kg/m 2 in Marfella s study. Inflammation assessed by CRP is related to metabolic disturbances such as obesity, hyperlipidemia, diabetes or metabolic syndrome [28,29]; and the MBPS has also been shown to be associated with glycemic abnormalities [30]. In the present study, the prevalence of subjects with metabolic disturbances might have been lower than that in Marfella s study, so that the correlation of hscrp to MBPS may also be relatively lower. Large vessel atherosclerosis, particularly severe carotid stenosis, is thought to be associated with inflammation and a risk factor for the incidence of stroke; however, we did not evaluate cerebral artery by MRA and carotid ultrasound. New-onset atrial fibrillation during the follow-up periods was not also assessed in this study, although it could have substantially contributed to the stroke incidence among hypertensive patients. These were limitations of the present study. 5. 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