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Severity of Helicobacter pylori Gastritis Predicts Duodenal Ulcer Recurrence S. MIEHLKE, E. BAYERDORFFER, N. LEHN, G. A. MANNES, A. SOMMER, W. HOCHTER, J. WEINGART, E. BASTEIN, R. HATZ & M: STOLTE Dept. of Gastroenterology, Hepatology and Infectious Diseases, University Hospital, Magdeburg; Dept. for Clinical Microbiology, Technical University of Munich, Munich; Dept. of Internal Medicine, Krankenhaus der Barmherzigen Briider, Munich; Dept. of Surgery, Klinikum GroBhadern, University of Munich, Munich; and Dept. of Pathology, Klinikum Bayreuth, Bayreuth, Germany Miehlke S, Bayerdorffer E, Lehn N, Mannes GA, Sommer A, Hkhter W, Weingart J, Bastlein E, Hatz R, Stolte M. Severity of Helicobacter pylori gastritis predicts duodenal ulcer recurrence. Scand J Gastroenterol 1996;31:856-862. Background: Helicobacter pylori gastritis is suggested to be the underlying condition leading to duodenal ulcer disease. The aim of the study was to investigate the relationship between chronic active H. pylori gastritis and the risk of duodenal ulcer (DU) recurrence. Methods: One hundred and eighty-eight patients were followed up with regard to the evolution of their H. pylori gastritis after they had received antibacterial or acid-suppressing treatment for their DU. Four weeks, 1 year, and 2 years after treatment and in the case of DU recurrence several morphologic indicators of gastritis were studied histologically in the antrum and corpus. Results: In patients who were cured of H. pylori infection a significant and long- lasting regression of all gastritis variables were observed. Patients with persistent H. pylori infection after antibacterial treatment showed only a temporary regression of all gastritis variables. In the overall group of patients who received acid-suppressive therapy there was no change in gastritis. However, in the subgroup of patients who received omeprazole monotherapy, no change in the antrum but a statistically significant increase of gastritis in the corpus was observed. The grade of antral gastritis at the end of treatment was significantly and positively correlated with the risk of DU recurrence and was independent of the kind of pretreatment (18.5% recurrences in grade-2 versus 86% in grade4 gastritis). Conclusions: The data show that the grade of gastritis is an important risk factor for duodenal ulcer recurrence. Cure of H. pylori infection is associated with healing of chronic H. pylori-associated gastritis. These data lend considerable support to the hypothesis that H. pylori gastritis is the most important factor among those leading to duodenal ulcer disease. Key words: Duodenal ulcer recurrence; Helicobacter pylori gastritis Stephan Miehlke, M.D., Dept. of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Magdeburg, Leipziger Str. 44,0-39120 Magdeburg, Germany urn: +49 391 6713125) In 1923 Konjetzny (1) reported that duodenal or gastric ulcer is always associated with chronic gastritis, and on the basis of his observations he speculated that chronic gastritis might be the underlying cause of peptic duodenal and gastric ulcers. After the isolation of Helicobacter pylori in 1982 (2) clinical trials involving antibacterial treatment have shown an improvement in chronic H. pylori-associated gastritis and that cure of H. pylori infection is associated with an absence of or a marked decrease in duodenal ulcer (DU) recurrence rates (3,4). However, data on the relationship between persistent H. pylori infection, the course of chronic gastritis, and its relationship to the risk of DU recurrence are sparse. The aim of the present study was to evaluate the relationship between the long-term course of chronic H. pylori gastritis and the risk of DU recurrence after antibacterial or acid-suppressive antiulcer treatment in patients who were previously enrolled in two separate treatment trials (5,6). PATIENTS AND METHODS Patient recruitment One hundred and eighty-eight patients with healed DU were followed up after randomly applied treatment with 40 mg omeprazole twice daily + 1000 mg amoxicillin twice daily for 10 days, followed by 20 mg omeprazole for a total of 6 weeks (n = 27) or 40 mg omeprazole twice daily, followed by 20 mg omeprazole for a total of 6 weeks (n = 25) (5); or 600mg bismuth subsalicylate (BSS) three times daily for 6 weeks + 1OOOmg amoxicillin twice daily for 10 days (n = 47) or 600 mg BSS monotherapy three times daily for 6 weeks (n = 44) or 300 mg ranitidine once daily at night for 6 weeks (n = 45) (6). Endoscopy and biopsy Endoscopies were performed 4 weeks after termination of treatment and after 1 and 2 years. At each endoscopic Scand J Gastroenterol Downloaded from informahealthcare.com by University of British Columbia on 11/18/14 For personal use only.

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Page 1: Severity of               Helicobacter pylori               Gastritis Predicts Duodenal Ulcer Recurrence

Severity of Helicobacter pylori Gastritis Predicts Duodenal Ulcer Recurrence

S. MIEHLKE, E. BAYERDORFFER, N. LEHN, G. A. MANNES, A. SOMMER, W. HOCHTER, J. WEINGART, E. BASTEIN, R. HATZ & M: STOLTE Dept. of Gastroenterology, Hepatology and Infectious Diseases, University Hospital, Magdeburg; Dept. for Clinical Microbiology, Technical University of Munich, Munich; Dept. of Internal Medicine, Krankenhaus der Barmherzigen Briider, Munich; Dept. of Surgery, Klinikum GroBhadern, University of Munich, Munich; and Dept. of Pathology, Klinikum Bayreuth, Bayreuth, Germany

Miehlke S, Bayerdorffer E, Lehn N, Mannes GA, Sommer A, Hkhter W, Weingart J, Bastlein E, Hatz R, Stolte M. Severity of Helicobacter pylori gastritis predicts duodenal ulcer recurrence. Scand J Gastroenterol 1996;31:856-862.

Background: Helicobacter pylori gastritis is suggested to be the underlying condition leading to duodenal ulcer disease. The aim of the study was to investigate the relationship between chronic active H. pylori gastritis and the risk of duodenal ulcer (DU) recurrence. Methods: One hundred and eighty-eight patients were followed up with regard to the evolution of their H. pylori gastritis after they had received antibacterial or acid-suppressing treatment for their DU. Four weeks, 1 year, and 2 years after treatment and in the case of DU recurrence several morphologic indicators of gastritis were studied histologically in the antrum and corpus. Results: In patients who were cured of H. pylori infection a significant and long- lasting regression of all gastritis variables were observed. Patients with persistent H. pylori infection after antibacterial treatment showed only a temporary regression of all gastritis variables. In the overall group of patients who received acid-suppressive therapy there was no change in gastritis. However, in the subgroup of patients who received omeprazole monotherapy, no change in the antrum but a statistically significant increase of gastritis in the corpus was observed. The grade of antral gastritis at the end of treatment was significantly and positively correlated with the risk of DU recurrence and was independent of the kind of pretreatment (18.5% recurrences in grade-2 versus 86% in grade4 gastritis). Conclusions: The data show that the grade of gastritis is an important risk factor for duodenal ulcer recurrence. Cure of H. pylori infection is associated with healing of chronic H. pylori-associated gastritis. These data lend considerable support to the hypothesis that H. pylori gastritis is the most important factor among those leading to duodenal ulcer disease.

Key words: Duodenal ulcer recurrence; Helicobacter pylori gastritis

Stephan Miehlke, M.D., Dept. of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Magdeburg, Leipziger Str. 44,0-39120 Magdeburg, Germany urn: +49 391 6713125)

In 1923 Konjetzny (1) reported that duodenal or gastric ulcer is always associated with chronic gastritis, and on the basis of his observations he speculated that chronic gastritis might be the underlying cause of peptic duodenal and gastric ulcers.

After the isolation of Helicobacter pylori in 1982 (2) clinical trials involving antibacterial treatment have shown an improvement in chronic H. pylori-associated gastritis and that cure of H. pylori infection is associated with an absence of or a marked decrease in duodenal ulcer (DU) recurrence rates (3,4). However, data on the relationship between persistent H. pylori infection, the course of chronic gastritis, and its relationship to the risk of DU recurrence are sparse.

The aim of the present study was to evaluate the relationship between the long-term course of chronic H. pylori gastritis and the risk of DU recurrence after antibacterial or acid-suppressive antiulcer treatment in patients who were previously enrolled in two separate treatment trials (5,6).

PATIENTS AND METHODS

Patient recruitment One hundred and eighty-eight patients with healed DU

were followed up after randomly applied treatment with 40 mg omeprazole twice daily + 1000 mg amoxicillin twice daily for 10 days, followed by 20 mg omeprazole for a total of 6 weeks (n = 27) or 40 mg omeprazole twice daily, followed by 20 mg omeprazole for a total of 6 weeks (n = 25) (5); or 600mg bismuth subsalicylate (BSS) three times daily for 6 weeks + 1OOOmg amoxicillin twice daily for 10 days (n = 47) or 600 mg BSS monotherapy three times daily for 6 weeks (n = 44) or 300 mg ranitidine once daily at night for 6 weeks (n = 45) (6).

Endoscopy and biopsy Endoscopies were performed 4 weeks after termination of

treatment and after 1 and 2 years. At each endoscopic

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Gastritis in DuodeMl Ulcer Disease 857

Table I. Study population

No. of patients free of duodenal ulcer recurrence (n)

End of 1 month after 1 year after 2 years after Treatment group treatment treatment treatment treatment

~ _ _ _ _ _

H. pylori-negative after 46 46 43 40

H. pylori-positive 70 67 41 28

H. pylori-positive after 72 54 22 15

antibacterial treatment

after antibacterial treatment

acid suppression

Table 11. Grade of gastritis in the antrum and corpus before and after treatment

Grade of gastritis Grade of gastritis Grade of gastritis Antrum Corpus Antrum Corpus Antrum Corpus

Helicobacter H. pylori-negative8 after H. pylori-positive after H. pylori-positive after pylori status antibacterial treatment antibacterial treatment acid suppression

Before treatment 3 2 3 2 3 2 End of treatment 2* * 1tt 2 1 3 2 4 weeks after treatment 2 t t t lttt 2 2 3 2

3 2 3 2 1 year after treatment I*** O*** 2 years after treatment l*** ot 2 1 2 2

Values are medians of the grading described in the methods and previously (9). **P < 0.0025; ***P < 0.01; tP < 0.005; ttP < 0.0025; tttP < 0.001 compared with the pretreatment status (Wilcoxon test). Q Cure of infection, checked 4 weeks after termination of treatment.

examination two biopsy specimens were taken from the antrum and two from the corpus and placed in neutral buffered formalin before histologic examination. Specimens were taken from both antrum and corpus of the stomach since H. pylori colonization in the stomach shows a patchy distribution (7), and also because omeprazole may suppress H. pylori colonization in the antrum but not in the corpus (8).

Histology Biopsy specimens were fixed immediately with 4% neutral

formalin and kept at room temperature. Thin sections were routinely prepared and stained using haematoxylin and eosin (H&E) and WarthinStany techniques. The gastritis-that is, lymphocyte and round-cell infiltration-was graded on a scale from 0 to 4, as previously described (9). In the same manner the density of H. pylori colonization, the activity of gastritis-that is, granulocyte infiltration, the degeneration of gastric surface cells, and gastric mucus depletion were graded (10). To show the development of the H. pylori-induced gastritis, a gastritis score (0-16) was created by adding together these four histologic factors.

All slides were read by one pathologist (M. Stoke), who was blinded to the preceding therapy. Eradication of H. pylori was determined as proposed by Marshall et al. (3).

Patient monitoring After ulcer healing, patients were contacted by phone every

3 months and asked whether they had experienced any

recurrence of symptoms or had taken any antiulcer or ulcerogenic medication such as Hz blockers, proton pump blockers, antacids, sucralfate, nonsteroidal anti-inflammatory drugs (NSAIDs), or acetylsalicylic acid. An endoscopic examination was performed whenever ulcer-like symptoms were reported.

Statistics The three groups of patients were compared with regard to

the median grades of all gastritis factors before treatment, at week 6, which was the end of treatment, at week 10, which was the cut-off time point 4 weeks after treatment for cure of H. pylori infection, and after 1 and 2 years. All comparisons were two-sided. Rate comparisons were made using the chi- square test, and the Wilcoxon test was used for comparison of histologic variables. The statistical analysis was performed with the statistical software package SPSS/PC+4.0 (SPSS Inc., Chicago, Ill., USA).

Ethical considerations '

University of Munich. The study was approved by the Ethics Committee of the

RESULTS

Between May 1990 and May 1993, 188 patients were followed up with regard to the evolution of their chronic gastritis and possible DU recurrence.

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858 S. Miehlke et al.

Gastritisscore in the Antrum

16

14

12

10

8 HP+ I m r anllbachrlal lreabnenl

6

4

2

n / u 0 6 Weeks 10 Weeks 1 Year 2 Years

Fig. 1. Gastritis score in the antrum before treatment, after 6 weeks (end of treatment), after 10 weeks, and after 1 and 2 years in patients who were Helicobacter pylori-negative (HP-) after antibacterial treatment, H. pylori-positive (HI'+) after antibacterial treatment, and H. pylori-positive after acid suppression, respectively. The gastritis score comprises the median grades of gastritis, activity, surface epithelial degeneration, and mucus depletion.

For evaluation purposes the patients were allocated to three groups with regard to their posttreatment H. pylori status (Table I): 1) H. pylori-negative after antibacterial treatment (omeprazole + amoxicillin, BSS + amoxicillin, BSS mono-

therapy) (n = 46); 2) H. pyfori-positive after antibacterial treatment (n = 70); and 3) H. pylori-positive after acid suppression (ranitidine, omeprazole) (n = 72).

The grude ofgastritis in the antrum and the corpus-that is,

Gastritisscore in the Corpus

" 0 6 Weeks 10 Weeks 1 Year 2 Years

Fig. 2. Gastritis score in the corpus before treatment, after 6 weeks (end of treatment), after 10 weeks, and after 1 and 2 years in patients who were Helicobacterpylori-negative (HP-) after antibacterial treatment, H. pylori-positive (HP+) after antibacterial treatment, and H. pylori-positive after acid suppression, respectively. The gastritis score comprises the median grades of gastritis, activity, surface epithelial degeneration, and mucus depletion.

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Gastritis in Duodenal Ulcer Disease 859

Table Ill. Median grade of gastritis before treatment and after 2 years or at the time point of duodenal ulcer (DU) recurrence

Grade of gastritis Grade of gastritis Grade of gastritis Remission DU recurrence Remission DU recurrence Remission DU recurrence

Helicobacter pylori H. pylori-negative* after H. pylori-positive after H. pylori-positive after status antibacterial treatment antibacterial treatment acid suppression

Before treatment 3 3 3 3 3 3 2 years after treatment 1 2 2 DU recurrence 4 4 4

~~~

The respective numbers of patients in the three groups (from left to right) were 23,45, and 15 for those who stayed in remission, and 4.42,

* Cure of infection, checked 4 weeks after termination of treatment. and 55 for those with DU recurrence.

lymphocyte and plasma cell infiltration-is shown in Table 11. After cure of H. pyfori infection, the grade of gastritis and the other gastritis variables summarized in the gastritis score decreased significantly in the antrum and corpus and remained low over time. In the overall group of patients who received acid-suppressive therapy there was no change in the grade of gastritis or the other gastritis indicators. However, in the subgroup of patients who received omepra- zole monotherapy for acid suppression no change in the antrum but a statistically significant increase of gastritis in the corpus (Figs. 1 and 2) was observed. With regard to the gastritis scores in the antrum and corpus there was no

In Table I11 the median grades of gastritis in the antrum are shown for patients who remained in remission during 2 years of follow-up in comparison with those with recurrent DU. The data show that patients with DU recurrence had much more severe gastritis than those who remained in remission.

The cumulative DU recurrence rates as a function of grade of gastritis at the end of treatment or grade of H. pyfori colonization at the 10-week examination are shown in Figs. 3 and 4.

DISCUSSION

statistically significant difference between patients who were Accumulating data from previous studies (3-6, 11, 12) treated with acid-suppressive therapy and those who were suggest that H. pylori-induced chronic active type-B gastritis unsuccessfully treated for H. pylori infection. is one of the most important factors in the pathogenesis of

Cumulative DU Relapse Rate (%) A-

loo fl 81.4

80 /

60

40

20

n V

Grade 0 Grade 3 Grade 4

Grade of HP Colonization at the 1 0-Week Examination

Cumulative DU Relapses within ... 1 Month B6 Months 1 Year 0 1.5 Years 0 2 Years

Fig. 3. Cumulative duodenal ulcer @U) recurrence in the groups of patients with different grades of Helicobacrer pylori (HP) colonization in the antrum at the 10-week examination (time point to check for cure of H. pylori infection). In 48 patients H. pylori infection was cured (grade 0). Grade 3 was diagnosed in 39, and grade 4 in 86 patients. Grade-1 and grade-2 H. pylori colonization occurred in only seven and eight patients, respectively (not shown in the figure). The difference in cumulative DU recurrence rates between the different gradings of H. pylori colonization was statistically significant by means of the log rank test (P < 0.0025 between grades 0 and 3; P = 0.27 between grades 3 and 4).

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Page 5: Severity of               Helicobacter pylori               Gastritis Predicts Duodenal Ulcer Recurrence

860 S. Miehlke et 01.

Cumulative DU Relapse Rate (%)

100 fl 86

a0 M 40

20

n U

Grade 2 Grade 3 Grade 4

Grade of Antral Gastritis at the End of Treatment

Cumulative DU Relapses within ... 1 Month 6 Months 1 Year 1.5 Years 0 2 Years

Fig. 4. Cumulative duodenal ulcer (DU) recurrence in the groups of patients with different grades of gastritis in the antrum at the 6-week examination. Grade 2 was diagnosed in 43, grade 3 in 91, and grade 4 in 54. Grade 1 gastritis occurred only in patients with successful cure of Helicobucterpylori infection at the 10-week and 1-year examination. The difference in the cumulative DU recurrence rates between the different gradings was statistically significant by means of the log rank test (P < 0.05 between grades 2 and 3; P < 0.01 between grades 3 and 4).

DU disease. Although the first treatment studies showed cure of H. pylori infection to be associated with a significant improvement in gastritis (3,4), we still have no data on the relationship between the severity of gastritis and the risk of duodenal ulcer recurrence, in particular in the case of persistent H. pylori infection. In an attempt to clarify this point, we have followed the evolution of chronic H. pylori gastritis in DU patients after various antiulcer treatment regimens in a sample of 188 patients over a period of 2 years, which is longer than all other observations on the course of gastritis published so far.

To grade the gastritis, we used a semiquantitative five- grade system, described earlier (9, 14), which in principle is very similar to the Sydney System (15,16). As additional factors we investigated the grade of replacement of gastric foveolar epithelium by regenerating epithelium and the grade of gastric mucus depletion, using the same semiquantitative five-grade system, which turned out to change parallel to the grade of H. pylori colonization, and grade and activity of gastritis. Our grading system extends the Sydney System somewhat, since our grading of the ‘minimal changes’ that account for about 5% of all findings and represent the borderline to normal is included in the ‘low-grade’ classifica- tion of the Sydney System. The suitability and reproducibility of our grading system has been confirmed by the results of clinical trials conducted by our group ( 5 6 ) and by a comparison with quantitative morphometric procedures (17).

In the event of cure of H. pylori infection we observed in

most patients nearly complete histologic healing of gastritis in the corpus of the stomach. In the antrum minimal infiltration of lymphocytes and plasma cells persisted after 1 year but returned to complete normality after 2 years in some patients. Complete regression of gastritis after cure of H. pylori infection has been reported by Rauws et al. (4) and by Valle et al. (11) so far in only a few patients, but Valle et al. used the Sydney System, which does not consider minimal changes of the gastric mucosa separately. Persistence of low-grade changes in the antrum has been described by Genta et al. (18), Marshall et al. (3), Bayerdorffer et al. (5), and others

In cases of persistent H. pylori infection after antibacterial treatment we found only a temporary decrease in the grade of all gastritis variables studied in the antrum and corpus.

In the overall group of patients who received acid- suppressive treatment there was no significant change in gastritis in the antrum and corpus. However, those patients who were treated with omeprazole monotherapy showed no change of gastritis in the antrum but a significant increase in the grade of gastritis and other gastritis variables in the corpus.

In several previous studies no biopsy specimens were taken from the corpus of the stomach (3,4,19-21). The progression of gastritis in the corpus seen in some of the patients during acid-suppressive treatment would appear to be a very important observation, which may explain several of the effects that sustained acid suppression may have on the

(1 9,20).

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Gastritis in Duodenal Ulcer Disease 861

natural course of chronic H. pylori gastritis (22,23). It has been suggested that hypoacidity may contribute to progres- sion of gastritis towards atrophy including that in the corpus, similar to that which is known to occur in patients after Billroth-I1 gastric resection (22,23) and in patients after vagotomy (24).

The disappearance of H. pylori was closely paralleled by a decrease in the grade of activity of gastritis, gastric surface cell degeneration, and mucus depletion. With the exception of the activity of gastritis, a study of these factok has only just begun by some other groups (25,26), and so far the effect of cure of H. pylori infection on these variables has not been reported.

The relation between gastritis in the antrum and duodenal ulcer recurrence was studied to test the hypothesis that chronic active H. pylori-associated gastritis is the most important factor in the pathogenesis of DU disease. Our current hypothesis on the possible development of DU disease originates in early observations that the antral area is relatively small and the corpus area relatively large in DU patients, corresponding to an increased parietal cell mass (27). H. pylori colonization in such patients leads to reduction in D- cell activity in the antrum (28) and thus to an exaggerated gastrin release (29) and subsequent acid production from the relatively large area of corpus mucosa. High acid load into the adjacent duodenal bulb may stimulate the development of gastric metaplasia (30), which will subsequently be colonized by H. pylori. H. pylori duodenitis is the precondition and shows continuous transition to duodenal ulceration. Although multiple factors are involved in the pathogenesis of DU, we have learned from many treatment studies (3-6,ll) that H. pylori gastritis is a necessary factor whose elimination leads to the absence of further attacks from duodenal ulceration.

Several reports have suggested a close relationship between the intensity of gastritis in the antrum and the grade of inflammation of gastric metaplasia in the duodenal bulb (3,13,31). Investigation of biopsy material from the duodenal bulb did not seem feasible in multicenter trials, since multiple biopsy specimens would be needed to adequately assess active inflammation of gastric metaplasia (3, 13). We therefore considered that the severity of gastritis in the duodenal bulb would be similar to that in the adjacent antrum, as already suggested by Marshall et al. (3) and decided to analyze the relationship between antral gastritis and duodenal ulcer recurrence. A possible relationship between gastritis in the stomach and duodenal ulcer has already been postulated by Konjetzny (l), and further evidence has been provided from the data reported by other authors (3,4). Initial semiquantitative data on this relation- ship has been presented by our group ($6 ) . In this study we have found a clear and highly significant association between grade of gastritis and risk of DU recurrence, which has not been described previously.

In conclusion, the data of this study showed that cure of H. pylori infection is associated with nearly complete healing of

chronic gastritis in the corpus and a minimal lymphocyte and plasma cell infiltration in the antral mucosa. On modifying the grade of gastritis by antibacterial treatment we found a clear association between grade of gastritis and risk of duodenal ulcer recurrence, which strongly supports the concept of chronic H. pylori gastritis as the underlying disease and the most important factor in the pathogenesis of duodenal ulcer disease.

ACKNOWLEDGEMENTS

We thank Prof. T. Sauerbruch and Prof. J. Eisenburg for their support during the preparation of the study and Ms. Ch. Sauerland, Ms. H. Miiller, Dr. A. Heinecke, and Dr. H. Ansari for their help in the documentation and statistical evaluation of the data. We thank the companies Astra (Hamburg, Germany), Rohm (Darmstadt, Germany), Cascan (Wiesbaden, Germany), Griinenthal (Stolberg, Germany), Becton & Dickinson (Heidelberg, Germany), and Heumann (Nurnberg, Germany) for their supply of drugs for the treatment phase of the study. Finally, we wish to thank Ms. Otahal for her secretarial help in the preparation of the manuscript.

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