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Just guessing : Antivirus software on your Domino server blocking read access to the NSF ?
Our environment is completely web based and we have over 50 applications. Our biggest application periodically will get a lock with the message "This database is currently in use by another person or process, and cannot be accessed at this time. In order to share a Notes database, it must be accessed via a Domino Server by all users of the database" and users will receive a 500 message from the web. This error has occurred 3 times since July requiring a restart of the services causing downtime for the entire Domino environment and many calls to our Help Desk. I have not been able to determine the cause but the Domino platform is not gaining any confidence with management. None of the fix packs for 10 mention this error but we are going to install FP3 with the hope that the issue is resolved but this has been an issue for a while and I have read forums where other orgs have had this issue and restarting the services is the only solution with no explanation as to why it happens.