The DOI matches its Crossref record; 31 of the 32 references it cites were found in a registry or an index; none of the 14 sources its claims cite is checked for support yet.
d-Cycloserine facilitates context-specific fear extinction learning
Open accessAbstract
D-cycloserine (DCS) may facilitate fear extinction learning, but the behavioral consequences and mechanisms behind this effect are not well understood at present. In this paper, we re-analyze data from previously reported null result experiments and find that rats showing above-median extinction learning during DCS treatment benefited from the drug, whereas rats showing below-median (and in this case little) extinction learning did not. Two additional experiments found that DCS facilitated extinction learning when specifically combined with a moderate, but not a small, number of extinction trials. DCS thus facilitates extinction learning only if the behavioral procedure first engages the extinction learning process. The benefits of the drug, however, were specific to the context in which extinction was learned--i.e., DCS did not prevent or influence the renewal of fear observed when the extinguished cue was tested in the original conditioning context.
Overview
AI snapshot
Written from the paper’s full text.
TL;DR
D-cycloserine (DCS) facilitated fear extinction only when the extinction procedure first engaged learning: rats that learned some extinction during the drug session benefited, and DCS helped with 12 but not 2 extinction trials. The benefit was context-specific and did not reduce renewal of fear in the original conditioning context.
Key findings
- In Experiment 1, a median split showed that rats above the median learned extinction during the DCS session, with a significant decrease in suppression across trial blocks, F(1, 22) = 54.80, whereas below-median rats did not, F(1, 22) < 1. DCS facilitated later test extinction only in above-median rats (group × block interaction, F(3, 66) = 2.95; significant on the second block, F(1, 22) = 4.73), with no DCS effect in below-median rats.
- In Experiment 2A, DCS facilitated extinction in the 12-trial group, F(1, 15) = 4.76, but not in the 2-trial group, F(1, 15) < 1. In Experiment 2B, the 12-trial DCS effect was F(1, 15) = 3.87, p = .03, one-tailed; pooled across 2A and 2B it was F(1, 31) = 8.69, two-tailed p = .006, while the 2-trial group did not approach significance, F < 1.
- DCS did not influence renewal. In Experiment 2A, renewal testing in Context A showed a significant difference between tests, F(1, 15) = 14.58, with no drug effect or interaction, Fs ≤ 2.01. In Experiment 2B, there were no drug effects or interactions, Fs ≤ 1.71, while freezing increased in Context A, F(1, 15) = 3.97, p = .03, one-tailed; pooled across 2A and 2B, F(1, 31) = 14.41, two-tailed p = .001.
Methods
- Experiment 1 used 48 female Wistar rats in a conditioned suppression procedure. Rats received fear conditioning in Context A, then four CS-alone extinction trials in Context B with DCS 30 mg/kg or saline injected 15 min before the session; tests occurred in Context B, and a median split on drug-session suppression ratios classified above- versus below-median extinction learning.
- Experiments 2A and 2B used 64 naive female Wistar rats (32 each). Rats received fear conditioning with two CSs in Context A; one CS was extinguished with saline in Context B and the other with DCS in Context C, with either 12 or 2 extinction trials and DCS doses of 15 or 30 mg/kg. Freezing was scored every 2 s, with interobserver correlations of r(62) = .97 and .92 for Experiments 2A and 2B; tests occurred in the extinction contexts and then in Context A for renewal.
- Statistical analysis used ANOVA with rejection criterion p < .05.
Limitations
- The paper states that Experiment 1 was correlational and could have been controlled by an unidentified third variable; Experiment 2 was designed to isolate the combination of DCS and CS re-exposure experimentally.
- The paper notes that its results did not replicate Lee et al.’s (2006) finding that DCS increased fear with minimal extinction training, and it lists procedural differences including number of CS re-exposures, session duration, and whether re-exposure occurred in a different context.
- Evident from the text: the experiments used only female Wistar rats, specific fear-conditioning preparations (conditioned suppression and conditioned freezing), limited DCS doses, and particular trial numbers, so the boundary conditions may not generalize beyond these procedures.
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Claims the paper makes
10 Not checked yet · 8 Own result · 7 Own interpretation · 3 Own method
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Freezing increased when the rats were returned to and tested in Context A, F (1,15) = 3.97, p = .03, one-tailed.”
§ D-cycloserine facilitates context-specific fear extinction learning > Experiment 2 > Results
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“As in Experiment 2, DCS did not influence the strength of the renewal effect observed when the animals were tested with the CSs in Context A.”
§ D-cycloserine facilitates context-specific fear extinction learning > Experiment 2 > Results
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Although these results indicate that DCS does facilitate extinction (loss of freezing) in rats given the larger number of trials, DCS did not influence the strength of the renewal effect observed when the animals were tested with the CSs in Context A.”
§ D-cycloserine facilitates context-specific fear extinction learning > Experiment 2 > Results
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“DCS did not prevent or influence the renewal of fear observed when the extinguished cue was tested in the original conditioning context.”
§ D-cycloserine facilitates context-specific fear extinction learning > Abstract
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: The renewal test had sufficient sensitivity or power to detect a DCS effect on renewal if such an effect were present.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“whether extinction was combined with DCS or saline, there was equivalent renewal of fear when the CS was removed from the extinction context and tested in the original conditioning context (Experiment 2).”
§ D-cycloserine facilitates context-specific fear extinction learning > General Discussion
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: The renewal test had sufficient sensitivity or power to detect a DCS effect on renewal if such an effect were present.
In the paper
“The present experiments did not replicate Lee et al.’s (2006) finding that DCS increased fear, rather than decreased fear, when it was administered with minimal extinction training.”
§ D-cycloserine facilitates context-specific fear extinction learning > General Discussion
What the sources say
- Not checked yetcites Lee et al.’s (2006) source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“When they separated subjects that had learned some extinction from those that had not, only the rats that had demonstrably learned some extinction benefited from the DCS.”
§ D-cycloserine facilitates context-specific fear extinction learning > Abstract
What the sources say
- Not checked yetcites Weber, Hart, and Richardson (2007)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“DCS thus facilitates extinction learning only if the behavioral procedure first engages the extinction learning process.”
§ D-cycloserine facilitates context-specific fear extinction learning > Abstract
plainconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: DCS is present in the brain during the extinction session when administered 15 minutes before the session.
None of the sources cited for this claim have been checked yet.
In the paper
“In humans, DCS administration can likewise facilitate the loss of fear resulting from exposure that causes incomplete fear loss in controls (acrophobia: Ressler, Rothbaum, Tannenbaum, Anderson, Graap, Zimand, Hodges, & Davis, 2004; social phobia: Guastella, Richardson, Lovibond, Rapee, Gaston, Mitchell, & Dadds, 2008; Hofmann, Meuret, Smits, Simon, Pollack, Eisenmenger, Shiekh, & Otto, 2006;”
§ D-cycloserine facilitates context-specific fear extinction learning > Abstract
What the sources say
- Not checked yetcites Ressler, Rothbaum, Tannenbaum, Anderson, Graap, Zimand, Hodges, & Davis, 2004 source
- Not checked yetcites Guastella, Richardson, Lovibond, Rapee, Gaston, Mitchell, & Dadds, 2008 source
- Not checked yetcites Hofmann, Meuret, Smits, Simon, Pollack, Eisenmenger, Shiekh, & Otto, 2006 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The benefits of the drug, however, were specific to the context in which extinction was learned—i.e., DCS did not prevent or influence the renewal of fear observed when the extinguished cue was tested in the original conditioning context.”
§ D-cycloserine facilitates context-specific fear extinction learning > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- It may state two separate claims as one. 6
- Probably not a substantial claim. 3
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“rats showing above-median extinction learning during DCS treatment benefited from the drug, whereas rats showing below-median (and in this case little) extinction learning did not.”
§ D-cycloserine facilitates context-specific fear extinction learning > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“rats that were above the median learned some extinction during the drug session, as indicated by a significant decrease in suppression across the trial blocks, F(1, 22) = 54.80, whereas rats below the median did not, F(1, 22) < 1.”
§ D-cycloserine facilitates context-specific fear extinction learning > Experiment 1 > Results
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Two additional experiments found that DCS facilitated extinction learning when specifically combined with a moderate, but not a small, number of extinction trials.”
§ D-cycloserine facilitates context-specific fear extinction learning > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In two unpublished experiments, DCS had no demonstrable effect on extinction learning.”
§ D-cycloserine facilitates context-specific fear extinction learning > Abstract
What the sources say
- Not checked yetcites Woods and Bouton (2006) source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Woods and Bouton (2006) found that although DCS facilitated fear loss in extinction, it did not weaken the renewal effect.”
§ D-cycloserine facilitates context-specific fear extinction learning > Abstract
What the sources say
- Not checked yetcites Woods and Bouton (2006) source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“They suggested that DCS enhanced memory “reconsolidation” (Nader, Schafe, & LeDoux, 2000) when it was combined with minimal CS exposure and enhanced extinction when it was combined with more.”
§ D-cycloserine facilitates context-specific fear extinction learning > Abstract
What the sources say
- Not checked yetcites Lee, Milton, and Everitt (2006) source
- Not checked yetcites Nader, Schafe, & LeDoux, 2000
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The correlations between the observers’ scores (each rat in both B and C) were r (62) = .97 and .92 for Experiments 2A and 2B.”
§ D-cycloserine facilitates context-specific fear extinction learning > Experiment 2 > Method
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
The paper relies on this without support.
DCS is present in the brain during the extinction session when administered 15 minutes before the session.
“the effectiveness of DCS was predicted by the extent to which animals learned extinction during the drug session (while the drug was in the brain)”
The paper relies on this without support.
The renewal test had sufficient sensitivity or power to detect a DCS effect on renewal if such an effect were present.
“DCS did not influence the strength of the renewal effect observed when the animals were tested with the CSs in Context A.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Hence, whether DCS has beneficial or detrimental effects appears to be linked with the sufficiency of fear learning achieved during (extinction) training.”
From D-cycloserine enhancement of fear extinction is specific to successful exposure sessions: evidence from the treatment of height phobia (2013) · cites this paper as [8]
In the citing paper
“Some preclinical data suggest that the DCS augmentation effect is moderated by the success of the extinction trials.”
From D-cycloserine enhancement of fear extinction is specific to successful exposure sessions: evidence from the treatment of height phobia (2013) · cites this paper as [8]
In the citing paper
“Likewise, in a re-analysis of a null-finding study (3) of DCS augmentation, Bouton and colleagues (8) subsequently performed a median split of their sample based on the extinction effects during the drug session; again, a significant DCS augmentation effect was seen only for the animals that had demonstrated stronger extinction learning.”
From D-cycloserine enhancement of fear extinction is specific to successful exposure sessions: evidence from the treatment of height phobia (2013) · cites this paper as [8]
In the citing paper
“Specifically, both Lee and colleagues (9) and Bouton and colleagues (8) found that DCS augmentation was evident only when a sufficient number of trials was offered for extinction learning.”
From D-cycloserine enhancement of fear extinction is specific to successful exposure sessions: evidence from the treatment of height phobia (2013) · cites this paper as [8]
In the citing paper
“Preclinical research indicates that the effect of DCS is to enhance whatever emotional learning has occurred; without sufficient extinction learning on drug, there is no or little beneficial outcome to enhance (8).”
From D-cycloserine enhancement of fear extinction is specific to successful exposure sessions: evidence from the treatment of height phobia (2013) · cites this paper as [8]
Statistics recomputed
Every reported test result, recomputed from its test statistic and degrees of freedom. A result shows as not adding up only once an independent check has confirmed it.
- ConsistentF(1, 15) = 3.87reported p = .03 · recomputed p = .068
“F(1,15) = 3.87, p = .03”
The paper states a one-tailed test
- ConsistentF(1, 15) = 3.97reported p = .03 · recomputed p = .065
“F (1,15) = 3.97, p = .03”
The paper states a one-tailed test
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ D-cycloserine facilitates context-specific fear extinction learning > General Discussion
“(e.g., see Bouton, 2004; Pearce, 1994; McNally & Westbrook, 2003)”
§ D-cycloserine facilitates context-specific fear extinction learning > References
“22. Pearce JM Similarity and discrimination: A selective review and a connectionist model Psychological Review 2004 101 587 607 7984708”
Citations
Cites
Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval
Nader, K., Schafe, G. E., & Le Doux, J. E. (2000) · Nature · doi:10.1038/35021052 · Cited by 2,706
Punishment and aversive behavior
Campbell, B. A., & Church, R. M. (1969) · Appleton-Century-Crofts eBooks · Cited by 1,989
Context and Behavioral Processes in Extinction: Table 1.
Bouton, M. E. (2004) · Learning & Memory · doi:10.1101/lm.78804 · Cited by 1,808 · cited 1×
“However, although extinction seems to eliminate fear, it does not reflect an erasure of the original fear learning (e.g., Bouton, 2004; Bouton, Westbrook, Corcoran, & Maren, 2006; Rescorla, 2001).”
BackgroundSelf-citationContext, ambiguity, and unlearning: sources of relapse after behavioral extinction
Bouton, M. E. (2002) · Biological Psychiatry · doi:10.1016/s0006-3223(02)01546-9 · Cited by 1,662 · cited 1×
“This principle has a number of implications for the success of therapies that rely on extinction for their beneficial effects (e.g., Bouton, 2002).”
BackgroundSelf-citationPredictability, surprise, attention, and conditioning
Kamin, L. J. (1967) · NASA Technical Reports Server (NASA) · Cited by 1,483
Some quantitative properties of anxiety.
Estes, W. K., & Skinner, B. F. (1941) · Journal of Experimental Psychology · doi:10.1037/h0062283 · Cited by 1,350
Conditional and unconditional components of post-shock freezing
Fanselow, M. S. (1980) · Pavlovian Journal of Biological Science · doi:10.1007/bf03001163 · Cited by 1,191
Probability of shock in the presence and absence of cs in fear conditioning.
Rescorla, R. A. (1968) · Journal of Comparative and Physiological Psychology · doi:10.1037/h0025984 · Cited by 1,067
Ressler, K. J., Rothbaum, B. O., Tannenbaum, L., Anderson, P., Graap, K., Zimand, E., Hodges, L., & Davis, M. (2004) · Archives of General Psychiatry · doi:10.1001/archpsyc.61.11.1136 · Cited by 1,063 · cited 1×
“In humans, DCS administration can likewise facilitate the loss of fear resulting from exposure that causes incomplete fear loss in controls (acrophobia: Ressler et al., 2004; social phobia: Guastella et al., 2008; Hofmann et al., 2006; obsessive–compulsive disorder: Kushner et al., 2007).”
BackgroundA modern learning theory perspective on the etiology of panic disorder.
Bouton, M. E., Mineka, S., & Barlow, D. H. (2001) · Psychological Review · doi:10.1037/0033-295x.108.1.4 · Cited by 1,017
Self-citation
Cited by
Sorted by citations
Lonsdorf, T. B., Menz, M. M., Andreatta, M., Fullana, M. A., Golkar, A., Haaker, J., Heitland, I., Hermann, A., Kuhn, M., Kruse, O., et al. (2017) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2017.02.026 · Cited by 837
“…beneficial effects of drugs enhancing extinction memory consolidation and exposure treatment were only observed in animals (Bolkan and Lattal, 2014; Bouton et al., 2008; Weber et al., 2007) and humans who did demonstrate successful extinction learning/treatment response to cognitive-behavioural…”
Neural and cellular mechanisms of fear and extinction memory formation
Orsini, C. A., & Maren, S. (2012) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2011.12.014 · Cited by 429
Singewald, N., Schmuckermair, C., Whittle, N., Holmes, A., & Ressler, K. J. (2015) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2014.12.004 · Cited by 390
“Along these lines, the extinction augmenting effects of DCS require the subject to show at least some ability to extinguish (Bolkan & Lattal, 2014; Bouton et al., 2008; Hefner et al., 2008; Smits et al., 2013b; Tomilenko & Dubrovina, 2007; Weber et al., 2007; Whittle et al., 2013).”
BackgroundBehavioral and neurobiological mechanisms of pavlovian and instrumental extinction learning
Bouton, M. E., Maren, S., & McNally, G. P. (2020) · Physiological Reviews · doi:10.1152/physrev.00016.2020 · Cited by 440
Self-citationSeeking a Spotless Mind: Extinction, Deconsolidation, and Erasure of Fear Memory
Maren, S. (2011) · Neuron · doi:10.1016/j.neuron.2011.04.023 · Cited by 259
“Interestingly, there have been reports that the extinction memory acquired under DCS is less likely to exhibit recovery (e.g., reinstatement) (Ledgerwood et al., 2004), although this outcome has not been universally reported (Bouton et al., 2008; Woods and Bouton, 2006).”
Background
Metadata
- Authors
- Bouton, M. E., Vurbic, D., & Woods, A. M.
- Affiliations
- University of Vermont (US)
- Corresponding author
- Bouton, Mark E.
- ORCID
- Bouton, Mark E.
- Venue
- Neurobiology of Learning and Memory
- Publisher
- Elsevier BV
- Published
- 2008-10
- Volume
- 90
- Issue
- 3
- Pages
- 504-510
- ISSN
- 1074-7427 (ISSN-L)
- PMC
- PMC2613791
- OpenAlex
- W2076008075
- Cited by
- 118
- References
- 32
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 3 · 2023: 2 · 2022: 4 · 2021: 2 · 2020: 1 · 2019: 4 · 2018: 5 · 2017: 11 · 2016: 4 · 2015: 9 · 2014: 16 · 2013: 11 · 2012: 15
- FWCI
- 4.65
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Neurobiology of Learning and Memory (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- D-cycloserine, fear extinction, extinction learning, fear renewal
- MeSH terms
- Animals, Antimetabolites, Association Learning, Behavior, Animal, Conditioning, Classical, Cycloserine, Environment, Extinction, Psychological, Fear, Female, Rats, Wistar, Rats
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