Teprenone improves gastric mucosal injury and dyspeptic symptoms in long term

nonsteroidal anti-inflammatory drug users

Yingying Gong§, Xinxin Huang*, Minhu Chen*, Lishou Xiong*

* §
Department of Gastroenterology and Hepatology, Department of Geriatrics, the First
Affiliated Hospital of Sun Yat-sen University, Guangzhou, China

Correspondence to: Lishou Xiong, MD& Ph.D, Department of Gastroenterology and

Hepatology, the First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan II Road,
Guangzhou, 510080, P.R. China.
Tel: 8620-87755766-8182 (O); Fax: 86-20-87332916
E-mail: xionglishou@263.net

Declaration of conflict of interest: None of the authors have any conflicts to declare.

This study was supported by the Natural Science Foundation of Guangdong Province, China
awarded to LX (Grant No: 2017A030313646).

Acknowledgments: We thank Liya Zhou in the third affiliated hospital of Peking university
for participating in this study.

This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process which may
lead to differences between this version and the Version of Record. Please cite this article as
doi:

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Abstract
Background and Aim: Nonsteroidal anti-inflammatory drugs (NSAIDs) is a major cause of
gastric mucosal lesions. In China, teprenone is frequently prescribed as a mucoprotective
agent, but the literature regarding their efficacy is limited. Our purpose was to address the
effects of teprenone on long-term NSAID-associated gastric mucosal lesions.
Methods: This study examined 369 patients taking NSAIDs for at least 12 weeks. Patients
without gastroduodenal ulcer and without Helicobacter pylori (H. pylori) infection on
endoscopy at baseline were randomized to receive either NSAID plus teprenone (150 mg/day)
or NSAID only for 12 weeks. Lanza scores was examined using endoscopy before and after
treatment and dyspeptic symptom scores are also analyzed.
Results: A total of 158 patients were randomized to teprenone group (n=74) or control group
(n=84) for 12 weeks. 71 of patients in teprenone group and 79 of patients in control group
were analyzed finally. After treatment the Lanza scores and dyspeptic symptom scores
decreased significantly in teprenone group, while increased in control group (P<0.05). The
changes of Lanza scores and dyspeptic symptom scores were higher in teprenone group than
control group (P<0.05). For subgroup analysis, the change in Lanza scores and dyspeptic
symptom scores improved significantly in teprenone group receiving long-term LDA
treatment, as well as in teprenone group receiving other NSAIDs treatment (P<0.05).
Conclusions: Teprenone may be an effective treatment choice of gastric mucosal injuries and
dyspepsia symptoms in patients who used NSAIDs chronically without H. pylori infection or
history of gastroduodenal ulcer.
Key words: teprenone, geranylgeranylacetone, non-steroidal anti-inflammatory drugs, gastric
mucosal injury, dyspeptic symptoms.
Introduction
Nonsteroidal anti-inflammatory drugs (NSAIDs) including low-dose aspirin (LDA) are
widely prescribed for rheumatic diseases and cardiovascular disease. Nevertheless, it is well
known that NSAIDs are associated with a wide range of adverse effects in dyspepsia and
peptic ulcer complication1,2. NSAIDs damage the gastric mucosa in the whole gut by two
mechanisms, a systemic effect associated with mucosal prostaglandin depletion derived from

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cyclooxygenase (COX) -1 and also a direct topical injury3. As gastric acid is closely involved
in the pathogenesis of NSAID-associated gastroduodenal mucosal injury, the concomitant use
of acid secretion-suppressing has been recommended to prevent NSAID-induced gastropathy,
such as proton pump inhibitors (PPI), and H2-receptorantagonists (H2RA) and prostaglandin
analogs (misoprostol)4-6. Although a short-term treatment regimen with PPIs might be
effective, long-term continuous use is not cost-effective7, and many have pointed out safety
concerns that include an increased the risks of infection8, the risks of fractures9, interaction
with clopidogrel10 and the risks of thromboembolism11, thus cannot be recommended.
Besides that, long term inhibition of acid secretion might lead to the development of chronic
atrophic gastritis12. Moreover, in clinical practice, misoprostol is associated with a high
incidence of side effects, such as diarrhea, abdominal pain, raising issues regarding
continuous administration6,13. Therefore, the therapy of choice for preventing upper
gastrointestinal injury associated with long-term NSAIDs treatment has not yet been fully
determined.
Teprenone, also known as geranylgeranylacetone (GGA), is a mucosal protective agent
with a low incidence of side effects that is employed to treat gastritis and gastric ulcers in
areas of Asia, including China and Japan. It is an acyclic isoprenoid compound with a
retinoid skeleton mainly as heat shock protein (HSP) inducing agent14,15. HSP promotes
protein folding, membrane passage and protects cells against gastric injury induced by
various types of stressors including NSAIDs, without affecting gastric acid secretion16. In
addition, teprenone has been also shown to stimulate prostaglandin E2 production which is a
key molecule involved in gastric ulcer repair processes17. Other mechanisms of its protection
have been proposed including inhibiting lipid peroxide formation or xanthine-xanthine
oxidase18, suppressing the production of interleukin-819 and stimulating of mucin secretion20.
As far as we know, many basic experiments confirmed that GGA might improve gastric
mucosal lesions induced by long-term NSAIDs treatment. Further clinical studies shown that
teprenone reduced erosion and bleeding significantly in gastritis patients with dyspeptic
symptoms and prevented the recurrence of peptic ulcers in subjects on LDA therapy21-23. In
addition, protection by teprenone has reported not only in NSAIDs-induced gastric mucosal

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injury but also in small intestinal mucosal injury24-26. However, the literature regarding
efficacy of the teprenone in the treatment and/ or prevention of gastric mucosal lesions and
dyspeptic symptoms in patients receiving long-term NSAIDs is still limited.
To avoid the effect of Helicobacter pylori (H. pylori), we therefore conducted a study in
patients without H. pylori infection in order to determine whether teprenone would improve
chronic NSAIDs-induced gastroduodenal mucosal injury and dyspepsia symptoms.

Methods
Patients
Patients were recruited from the out-patient departments of rheumatology and cardiovasology
in Guangzhou and Beijing hospitals between August 2008 and February 2011. Inclusion
criteria were that patients required long-term NSAIDs or low dose of aspirin (LDA) (100
mg/d). Long-term NSAIDs or LDA treatment was defined as the use of any NSAID more
than 5 days per week for at least 3 months and required continual NSAID treatment after the
study. All patients were between 18 and 80 years of age, negative for H. pylori infection and
had no peptic ulcer was detected on endoscopy at the baseline. Exclusion criteria were as
follows: presence of peptic ulcer; a combination of two or more NSAIDs, or anticoagulants;
concurrently with gastroprotective agents, including PPIs, H2RAs, and misoprostol within 1
month before recruitment; a previous history of gastrointestinal ulcer or bleeding; a history of
H. pylori eradication; previous gastrointestinal surgery; a severe concomitant disease or
alarming symptoms or signs; a known allergy to the study medication, or were pregnant.
Concurrent use of hypotensive agents or hypolipidemic drugs for cardiovascular diseases,
low-dose steroids (≤20 mg prednisolone daily) and methotrexate for musculoskeletal
disorders drugs was allowed. The study was conducted in accordance with the Helsinki
Declaration and approved by the institutional review board of the National Ministry of
Science and Technology (2007BAI04B02) and the ethics committees of each participating
hospital. This trial has been registered with ClinicalTrials.gov, number NCT01547559. All
patients provided written informed consent.

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Procedures
After confirming the patients had no peptic ulcer and H. pylori un-infected on endoscopy at
the start of the study, eligible patients were randomized to teprenone group or control group
using a list of computer-generated consecutive numbers in proportions of 2: 1 within blocks
of six. Both study centers were provided with individually sealed coded envelopes containing
the treatment for each patient. Each treating physician practiced at only one center. Patients
were assigned to receive either NSAID treatment plus teprenone (50 mg three times daily) or
NSAID treatment only for 12 weeks. Each patient underwent endoscopic examination after
treatment.

Follow up
Appointments with the study physician were scheduled every 4 weeks after study initiation.
At baseline, patients were questioned about their smoking habits, alcohol consumption,
height, body weight, underlying diseases, concurrent medical illnesses, drug history and
history of gastroduodenal ulcers. Each patient was physically examined at each visit to rule
out any possible severe condition. Blood analysis including complete blood counts, liver and
renal function tests and urinalysis were performed at the start and end of the study or at any
time deemed necessary by the physician. Unscheduled visits were encouraged when
dyspeptic complaints or adverse events occurred and unscheduled endoscopy was performed
when clinically indicated.

Endoscope
Endoscopy was performed before and 12 weeks after treatment by the same single,
experienced endoscopist who were blinded for treatment allocation in each center. The
numbers of erosions and ulcers was evaluated separately using a modified Lanza score.
Scores used in the present study were as follows: 0 (no erosions), 1 (<2 erosions but confined
to one area), 2 (3~5 erosions but confined to one area), 3 (<6 erosions in each of two areas,
with a total of <10 erosions), or 4 (>10 erosions in three areas), 5 (ulcer)27. Three biopsy
specimens were taken from the antrum, corpus and fundus of the stomach; one was used in a

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rapid urease test (RUT, Huitai Medical Science and Technology Co. Ltd, Shanghai, China),
two were fixed in 10% buffered formalin, embedded in paraffin, cut into sections and stained
with Hematoxylin and Eosin (H&E) for histological analysis. All stained biopsy specimens
were examined by a single expert pathologist who was blinded for clinical data. A patient
was considered H. pylori uninfected when both rapid urease test and histology were negative.

Symptoms
At all visits, patients were questioned about dyspepsia. Dyspeptic symptoms were assessed
with five categories (epigastric pain, postprandial fullness, early satiety, epigastric discomfort,
and epigastric burning) on the gastrointestinal symptom rating scale. The severity of
dyspepsia was graded as 0 (none), 1 (mild: easily tolerated), 2 (moderate: interfering with
normal activities), or 3 (severe: incapacitating and inability to perform normal activities)28.

Outcomes
The primary endpoint of this study was determined according to the Lanza score by
endoscopy findings. Therapeutic effect was shown in decreasing the Lanza score at 12 weeks
from baseline in each group and comparison of the changes in the score before and after
medication administration between the two groups. The secondary endpoint was determined
according to dyspepsia symptom score. The improvement of the dyspepsia symptoms was
shown in decreasing the dyspepsia symptom score in each group and comparison of the
changes in the score before and after administration between the two groups.

Statistical analysis
Measurements are expressed as mean (SD) or mean (95% confidence interval). Differences
between groups were compared by a two-tailed Fisher's exact test, Pearson χ2 test and
Wilcoxon rank sum test. Wilcoxon matched-pairs signed rank tests were used to compare
ordered categorical data within each group. The two-sided level of significance was set at p <
0.05. All statistical analyses were performed with the SPSS 19 statistical package (IBM).

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Results
Between August 2008 and February 2011, 369 eligible patients receiving chronic NSAIDs
agreed to take part in the trial and were assessed endoscopically after screening. H. pylori
infection and/or peptic ulcers were found in 211 patients. 158 of patients who had no ulcer
and negative H. pylori infection were randomized to receive pharmacotherapy by either
teprenone or control group (Fig. 1). Of these patients, four patients did not return for
post-treatment endoscopy: 1 in teprenone group, and 3 in the control group. In the teprenone
group, one patient took teprenone therapy for less than 7 days and one withdrew the NSAID
because of gastrointestinal upset. In control group, one patient took esomeprazole and one
stop taking the NSAID by himself because of gastrointestinal upset. Finally, 71 patients in
teprenone group and 79 patients in control group qualified for comprehensive analysis.
At baseline, none of the patient characteristics was significantly different between the
two groups (Table 1). Ninety-two (57.6%) patients took LDA; 48 (30%) took COX-2
preferential NSAIDs, 11 (7%) were receiving conventional NSAIDs, and 6 (3.8%) were
treated with a coxib.
At 12 weeks, gastroduodenal ulcers were diagnosed in 5 (6.7%) patients in the control
group ( 2 gastric and 3 duodenal ulcers ) and none in teprenone group. Two of the ulcers were
diagnosed in patients combined with steroids. No patient developed gastrointestinal bleeding
or perforation during the total study period of 12 weeks. There was no sever atrophic change
in our endoscopic findings.
Regarding the change in Lanza score, in teprenone group the Lanza score improved
significantly from 0.90 (0.69-1.11) [Mean (95% confidence interval)] to 0.25 (0.12-0.38)
after medication (p < 0.0001). In control group, the Lanza score was worse significantly from
0.63 (0.43-0.83) to 1.60 (1.31-1.90) after 12 weeks (p < 0.0001) (Table 2). There was
significant difference in the magnitude of the change in Lanza scores between teprenone
[-0.65 (-0.83- -0.46)] and control group [1.05 (0.8-1.3)] (p < 0.0001, Table 2).
The change in dyspeptic symptom scores increased significantly in control group from
1.11 (0.85-1.37) to 1.44 (1.17-1.70) (p = 0.001), while declined significantly in the teprenone

group from 1.51 (1.24-1.78) to 0.65 (0.47-0.83) after 12 weeks (p < 0.0001, Table 2）. There

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was significant difference in the magnitude of the change in dyspeptic symptom scores
between teprenone group [-0.86 (-1.07--0.65)] and control group [0.39 (0.14-0.64)] (p <
0.0001, Table 2). No patients developed severe dyspepsia symptoms requiring rescue
treatment.
We analyzed the change in Lanza score and dyspeptic symptom scores by taking
long-term LDA or other NSAIDs treatment. The change in Lanza scores and dyspeptic
symptom scores improved significantly in teprenone group receiving long-term LDA
treatment, as well as in teprenone group receiving other NSAIDs treatment (Fig. 2).
All subjects completed the study with no serious adverse events. No abnormalities were
detected on clinical examination or blood tests throughout the study period.

Discussion
Maintenance use of NSAIDs is often complicated by NSAID-gastropathy, which is
characterized by dyspepsia, superficial mucosal damage, and ulcer. Currently, the most
widely accepted treatment is acid suppression therapy or treatment with mucoprotective
drugs. Studies have also shown that long-term inhibition of acid secretion might lead to the
development of chronic atrophic gastritis12. A costly outlay makes it difficult to prescribe
PPIs for long-term treatment of NSAID-associated gastric mucosal lesions7. So-called
mucoprotective drugs and H2RAs have been reported to have positive effects on the
treatment of gastric mucosal lesions when NSAIDs are discontinued. However, these positive
effects are reduced when NSAID therapy is continued29,30. Moreover, some well-known
gastrointestinal side effects of misoprostol have limited its clinical use13. Thus, it is necessary
to consider how best to approach the prevention and treatment of chronic NSAIDs-induced
gastrointestinal mucosal damage. In the present study, we selected teprenone as a mucosal
protective agent which is employed to treat gastritis and gastric ulcers in areas of Asia. The
results of our study demonstrated that teprenone improved the outcome of gastric mucosal
lesions in chronic NSAID users without H. pylori infection or history of gastroduodenal
ulcer.
Although many experimental studies proved the protection against NSAIDs-induced

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gastric mucosal injury, there are lack of clinical studies in evaluating the effects of teprenone
and the conclusions were different. Previous results in the literature were based on studies
carried out mainly in Japan. When compared with cimetidine, teprenone reduced erosion and
bleeding significantly in gastritis patients with dyspeptic symptoms31. In contrast, it has been
shown that teprenone was insufficient for treatment of the gastroduodenal mucosal injuries
under use of LDA, while famotidine was better22. In addition, a Japanese study demonstrated
that 8.6% of teprenone-treated patients developed erosive oesophagitis de novo and around
21% had recurrent, while the recurrent rate of rabeprazole group was 1.4% in LDA users21.
Therefore, the mucosal protection effect of teprenone has been questioned by non-Asian
experts. Despite these controversies, we provided the evidence that GGA may also be a useful
agent against NSAID-induced gastric injury without history of peptic ulcer or infection of H.
pylori. It may be important for clinicians to prevent NSAID-associated ulcers with bleeding.
Although the long list of potential adverse effects associated with long-term PPI therapy, the
overall quality of evidence for PPI adverse effects is low to very low. Long-term PPI therapy
was still recommended for NSAID bleeding prophylaxis if high-risk32,33. However, the
preventive treatment is still a debate issue in patients who were in low risk of ulcer
complications. A previous report shown that monotherapy with GGA, prevented the
development of lesions of esophagus to the small intestine and that combination therapy with
PPIs may not be necessary for patients without high risk of ulcer25. Therefore, whether GGA
therapy could prevent NSAID-associated ulcer and bleeding especially in patients with mild
or moderate risk is needed to investigated. Meanwhile, the clinical trial for comparison of
long-term GGA and PPIs/ H2Ras treatment against NSAID-induced gastric mucosal injury
and bleeding should also be investigated.
In fact, GGA probably have many advantages in clinic use. Firstly, GGA induces HPSs
synthesis not only in gastric mucosal but also in other organs including intestine24, liver34,
lung35, heart36, retina37 and central nervous system38. Many previous studies reported that the
NSAIDs-induced small/large intestinal mucosal injuries could markedly prevented by GGA,
not PPIs or H2RAs24-26. The mainly explanation is the protection of GGA is thought to occur
through induction of HSP independent of acid suppression14,15. Secondly, many animal

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experiments confined the cardioprotective effects of GGA including protecting against
ischemia-reperfusion injury, preventing myocardial injury from doxorubicin, improving
insulin resistance and attenuating endothelial inflammation39. Therefore, whether GGA can
be more beneficial to patients with cardiovascular disease than PPIs is not known and clinical
studies are required to confirm the protective effects. Thirdly, many patients who receive
long-term NSAID therapy have difficulty discontinuing these drugs, making therapeutic
performance during ongoing NSAID therapy more important. In our study, teprenone
improved not only the gastric mucosal injury but also dyspeptic symptoms in about 52.1% of
the patients. Similar results were reported in a previous study showed that teprenone
improved the patients with moderate dyspepsia 31,40,41. Fourth, it has been reported that GGA
might decreases the activity index and colony density of H. pylori in the corpus of the
stomach19. It is indicated that GGA might have better beneficial effect in patients with H.
pylori infection. However, few studies found that teprenone did not exert a good therapeutic
effect on gastric mucosal injuries under use of LDA in the presence of H. pylori infection22.
Our results provided evidence that GGA was of benefit in long-term NSAID users without H.
pylori infection. Therefore, the relationship between GGA and H. pylori infection is needed
to further investigated. Fifth, in line with previous studies, GGA did not cause any symptoms
or abnormalities during our study period which indicated GGA might be a safe agent.
This study has the following limitations. First, most of the clinic trial evaluated the
effects of teprenone on LDA-associated gastric injury21,22. Here, we did not specify the type
of NSAIDs or limit the drugs. This study was designed to accurately mirror real clinical
practice, in which patients take various types of NSAIDs and agents to treat rheumatoid and
cardiovascular diseases. There were no significant differences about the basic treatment
regimens among the two groups. The results which teprenone significantly improved gastric
mucosal injuries and dyspepsia symptoms in patients receiving low dose of aspirin were the
same as that in patients receiving other NSAIDs treatment. Second, we also did not utilize the
groups treated by PPIs or H2RAs as a positive control or placebo as a negative control. Thus,
the effects of GGA on NSAID-induced gastric mucosal injury, especially comparison with
PPIs or H2Ras, should be investigated in further clinical trial. Third, long-term clinical course

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after week 12 is unknown. We hope to demonstrated in the future whether teprenone is
effective and safe for long-term treatment on gastroduodenal mucosal injury in chronic
NSAIDs users. Fourth, there are individual differences in NSAID/LDA-associated
gastroduodenal mucosal injury. Thus, a prospective, double-blind, placebo-controlled,
2-period, cross-over study is needed to clarify the effects of teprenone.
In summary, we investigated the efficacy of the treatment in patients with long-term
NSAIDs by a randomized prospective clinical trial comparing teprenone and control.
Endoscopic evaluation revealed that the Lanza scores was improved in teprenone group, with
no clinically significant adverse drug reactions. So as the dyspeptic symptom scores. The
results of our study suggest that teprenone may be an effective treatment choice of gastric
mucosal injuries and dyspepsia symptoms in patients who used NSAIDs chronically without
H. pylori infection or history of gastroduodenal ulcer.

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Table 1 Baseline characteristics of the patients in the two groups.
Teprenone
Control group
Characteristic group P-value
(n = 84)
(n = 74)
Age, years 54 ± 20 55 ± 18 0.697
Male/female 37/37 40/44 0.765
BMIa, kg/m2 21.9 ± 2.7 21.0 ± 2.5 0.876
Current smokers 12 (16) 11 (13.1) 0.579
Alcohol use 6 (8) 10 (11.9) 0.43
Primary diseases
Rheumatic disease 29 (39.2) 36 (42.9) 0.64
Cardiovascular disease 44 (59.5) 46 (54.8) 0.552
Cerebrovascular disease 1 (1.4) 2 (2.4) 0.636
NSAIDsb treatment
Conventional NSAIDs
3 (4.1) 8 (9.5) 0.178
(indomethacin, diclofenac, loxoprofen)
Cyclooxygenase-2 preferential NSAIDs
23 (31.1) 25(29.8) 0.857
(meloxicam, lornoxicam, nimesulide)
Coxib
3 (4.1) 3 (3.6) 0.874
(celecoxib, eloricoxib)
Aspirin 45 (60.8) 48 (57.1) 0.64
Duration of NSAIDs administration, months 14.4 ± 11.3 11.4 ± 10.5 0.082
Concurrent use of corticosteroids 2 (2.7) 6 (7.1) 0.204
Data are presented as the number of patients or the means ± SD; other values are numbers of
patients (%) unless noted. a Body-mass index, calculated as weight in kilograms divided by
the square of the height in meters. b the dose of NSAIDs: indomethacin (50 mg/d), diclofenac
(75 mg/d), loxoprofen (180 mg/d), meloxicam (8 mg/d), lornoxicam (8 mg/d), nimesulide
(100 mg/d), celecoxib (200 mg/d), eloricoxib (60 mg/d), aspirin (100 mg/d). *P <0.05.
Table 2 Chang in the Lanza and dyspepsia symptom scores of the control group and

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 teprenone group before and after 12 weeks of treatment.
n Baseline Post-treatment Change after treatment
(12 weeks) (week 12-baseline)

Lanza scores
Control group 79 0.63 (0.43-0.83) 1.60 (1.31-1.90) * 1.05 (0.8-1.3)
Teprenone group 71 0.90 (0.69-1.11) 0.25 (0.12-0.38) * -0.65 (-0.83- -0.46) #
Dyspepsia symptom scores
Control group 79 1.11 (0.85-1.37) 1.44 (1.17-1.70) * 0.39 (0.14-0.64)
Teprenone group 71 1.51 (1.24-1.78) 0.65 (0.47-0.83) * -0.86 (-1.07--0.65) #
#
Mean (95%CI); CI, confidence interval; * post-treatment vs baseline, P<0.05; teprenone
group vs control group, P<0.05.

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Figure 1 Number of enrolled subjects and the number in the analysis set.

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Figure 2 Comparison of the changes in the Lanza score between control and teprenone group
according to long-term LDA (a) or other NSAIDs (b) treatment. Comparison of the changes
in dyspepsia symptom score between control and teprenone group according to long-term
LDA (c) or other NSAIDs (d) treatment. Mean ± SD; *P<0.05.

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