After all these years I'm still learning that Apache's own configuration can dramatically effect server performance. In this case, more so than the MySQL configuration.
KeepAliveTimeout on my server was set to 8 seconds. Since I have this signature script doing 1,750,000+ impressions a day, I had a boatload of connections in "waiting" mode - 256 of them in fact. 256 * 8MB httpd process is 2GB itself with no room for MySQL to run.
I lowered by KeepAliveTimeout to 2 and it had a dramatic effect on my server performance. I'm lowered the number of servers than can run down to 180 to fit within my membery limits and also considering dropping my timeout limit to 1.
Since doing this I've seen a dramatic reduction in the use of memory by Apache processes and a boot in site performace (pages taking 2.5 seconds to process are now taking half that time).
So, while tuning MySQL, you will probably want to look at your Apache configuration, too.
