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In the MOTU setup, you have to tell it what output goes to the MAINS.
After that, in Audio MIDI Setup, tell it to direct sound to the MOTU unit, and under Speakers, set both STEREO and MULTICHANNEL to the proper audio stream.
I could be wrong, but I don't think you want to be using the PCI-424 SMPTE as the clock source. The main reason I say this is because nowhere in your message did you mention an external SMPTE source, which would normally be required. It does sound like a word clock issue ... and I've had more than m...